Haematopoietic-prostaglandin D2 synthase inhibitors

ABSTRACT

The present invention generally relates to compounds that inhibit haematopoietic-prostaglandin D 2  synthase (H-PGDS), to compositions containing them and to their use in treating or preventing conditions and diseases associated with H-PGDS, such as allergies and inflammation.

FIELD OF THE INVENTION

The present invention generally relates to compounds that inhibithaematopoietic-prostaglandin D₂ synthase (H-PGDS), to compositionscontaining them and to their use in treating or preventing conditionsand diseases associated with H-PGDS, such as allergies and inflammation.

BACKGROUND OF THE INVENTION

Bibliographical details of various publications referred to in thisspecification are collected at the end of the description.

The reference in this specification to any prior publication (orinformation derived from it), or to any matter which is known, is not,and should not be taken as an acknowledgment or admission or any form ofsuggestion that that prior publication (or information derived from it)or known matter forms part of the common general knowledge in the fieldof endeavour to which this specification relates.

Many non-steroidal anti-inflammatory drugs, such as aspirin andibuprofen, act by inhibiting cyclooxygenase, which in turn affectsproduction of various prostaglandins including prostaglandin H₂ (PGH₂),prostaglandin D₂ (PGD₂), prostaglandin E₂ (PGE₂), prostaglandin F_(2α)(PGF_(2α)), prostacyclin (PGI₂) and thromboxane (TX) A₂.

As each prostaglandin has different biological activities,cyclooxygenase inhibition may impact on a number of biological processeswith adverse effects. For example, this has been known to includegastric toxicity and cardiovascular complications associated withprostacyclin loss. Consequently, targeting the production of particularprostaglandins downstream of cyclooxygenase provides a much morespecific biological effect that avoids such complications.

PGD₂ is a major pro-inflammatory mediator of the allergic response andis known to have roles in body temperature regulation, sleep-wakeregulation, relaxation of smooth muscle, tactile pain response,bronchoconstriction, and inflammation. It is readily detected in nasaland bronchial lavage fluids of patients with asthma, allergic rhinitis,atopic dermatitis, and allergic conjunctivitis. PGD₂ triggers a range ofbiological effects consistent with a pathological role in asthma andallergy, including airways eosinophilia, obstruction, hypersensitivityand mucus hypersecretion. Compounds that inhibit PGD₂ production aretherefore attractive targets for drug development.

PGD₂ is active in both the central nervous system and peripheraltissues. Production of PGD₂ is performed by two genetically distinctPGD₂ synthase (PGDS) enzymes: brain-type-PODS (L-PGDS) andhaematopoietic-PGDS (H-PGDS). L-PGDS expression in mammals appears to bemostly restricted to the central nervous system, testis and heart. Incontrast, PGD₂ synthesis in peripheral tissues is likely to be throughH-PGDS.

Targeting the inhibition of PGD₂ synthesis may allow mediation ofpro-inflammatory responses without the side effects of cyclooxygenaseinhibition. There is therefore a need for small molecules that inhibitH-PGDS.

SUMMARY OF THE INVENTION

The present invention is predicated in part on the discovery thatcompounds of formula (I) inhibit H-PGDS. This discovery has been reducedto practice in novel compounds, compositions containing them and inmethods for their preparation and use, as described hereinafter.

Some compounds of the present invention advantageously exhibitselectivity for H-PGDS over cyclooxygenases and other prostaglandinsynthases.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows results of H-PGDS inhibitory activity of compound 3 inmouse primary bone marrow-derived macrophages (BMM).

FIG. 2 depicts results from experiments to characterise compound 3 PGD₂inhibition selectivity in mouse primary bone marrow-derived macrophages(BMM).

FIG. 3 shows results from experiments to characterise compound 3 PGD₂inhibition in human megakaryocytes.

FIG. 4 shows results from experiments to characterise COX1 and COX2inhibition by compound 3.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

In one aspect of the invention, there is provided a method of treatingor preventing a haematopoietic-prostaglandin D₂ synthase associateddisease or condition, comprising administering to a subject an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof:

wherein

-   -   Y is —N— or —CH—;    -   X is —NH—, —O—, —S—, —N═CH— or —CH═N—;    -   R¹ is optionally substituted thienyl or optionally substituted        thiazolyl;    -   R² is selected from —C(═O)—NR³R⁴, —C(═S)—NR³R⁴, —CH₂—CHR⁵R⁶,        —CH═CR⁵R⁶, —C≡CR⁷, —CH₂—OR⁷, —C(═O)—OR⁷, —CH₂—NR³R⁴,        —CH₂—C(OH)R⁵R⁶, —CH(OH)—C(OH)R⁵R⁶, —C(═O)—NH—NR³R⁴,        —C(═O)—NH—OR⁷, —P(═O)(OH)—NR³R⁴, —NH—C(═O)—NR³R⁴,        —O—C(═O)—NR³R⁴, —CH(CF₃)—NR³R⁴, and

-   -   Z is selected from —CH₂— or —NH—;    -   R³ is selected from —CHR⁸R⁹, —C₀₋₆alkyl-R¹⁰, —C₂₋₆alkenyl-R¹⁰,        and —C₂₋₆alkynyl-R¹⁰;    -   R⁴ is selected from hydrogen, hydroxyl, alkyl, haloalkyl,        alkenyl, and alkynyl; or R³ and R⁴ taken together form a        heterocyclyl or heteroaryl ring;    -   R⁵ is selected from —CHR⁸R⁹, —C₀₋₆alkyl-R¹⁰, —C₂₋₆alkenyl-R¹⁰,        and —C₂₋₆alkynyl-R¹⁰;    -   R⁶ is selected from hydrogen, hydroxyl, alkyl, alkenyl, and        alkynyl; or R⁵ and R⁶ taken together form a cycloalkyl,        cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;    -   R⁷ is selected from —CHR⁸R⁹, —C₀₋₆alkyl-R¹⁰, —C₂₋₆alkenyl-R¹⁰,        and C₂₋₆alkynyl-R¹⁰;    -   R⁸ is selected from —CO₂H, —CONH₂, —CONR¹⁶—CHR¹⁷—CONH₂,        —CONR¹⁶—CHR¹⁷—CO₂H, cycloalkyl, cycloalkenyl, aryl,        heterocyclyl, heteroaryl, —C₁₋₆alkylR¹⁰, —C₂₋₆alkenylR¹⁰ and        C₂₋₆alkynylR¹⁰;    -   R⁹ is selected from hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H,        —C₀₋₆alkylCONH₂, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH,        —C₀₋₆alkylSC₁₋₆alkyl, —C₀₋₆alkylNHC(═NH)NH₂,        —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl, —C₀₋₆alkylheterocyclyl and        —C₀₋₆alkylheteroaryl;    -   R¹⁰ is selected from cycloalkyl, cycloalkenyl, aryl,        heterocyclyl and heteroaryl;    -   R¹⁶ is selected from hydrogen, hydroxyl, alkyl, haloalkyl,        alkenyl, and alkynyl; and    -   R¹⁷ is selected from hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H,        —C₀₋₆alkylCONH₂, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH,        —C₀₋₆alkylSC₁₋₆alkyl, —C₀₋₆alkylNHC(═NH)NH₂,        —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl, —C₀₋₆alkylheterocyclyl and        —C₀₋₆alkylheteroaryl;    -   wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        aryl, heterocyclyl and heteroaryl are optionally substituted        with one or more optional substituents.

In one embodiment, the compound of formula (I) is a compound of formula(II) or a pharmaceutically acceptable salt thereof:

wherein

-   -   Y is —N— or —CH—;    -   L and M are independently selected from N and CR¹³, provided        that both L and M are not N;    -   R² is selected from —C(═O)—NR³R⁴, —C(═S)—NR³R⁴, —CH₂—CHR⁵R⁶,        —CH═CR⁵R⁶, —C≡CR⁷, —CH₂—OR⁷, —C(═O)—OR⁷, —CH₂—NR³R⁴,        —CH₂—C(OH)R⁵R⁶, —CH(OH)—C(OH)R⁵R⁶, —C(═O)—NH—NR³R⁴,        —C(═O)—NH—OR⁷, —P(═O)(OH)—NR³R⁴, —NH—C(═O)—NR³R⁴,        —O—C(═O)—NR³R⁴, —CH(CF₃)—NR³R⁴, and

-   -   Z is selected from —CH₂— or —NH—;    -   R³ is selected from —CHR⁸R¹¹, —C₂₋₆alkenyl-R¹⁰, and        —C₂₋₆alkynyl-R¹⁰;    -   R⁴ is selected from hydrogen, hydroxyl, alkyl, haloalkyl,        alkenyl, and alkynyl; or R³ and R⁴ taken together form a        heterocyclyl or heteroaryl ring;    -   R⁵ is selected from —CHR⁸R⁹, —C₀₋₆alkyl-R¹⁰, —C₂₋₆alkenyl-R¹⁰,        and —C₂₋₆alkynyl-R¹⁰;    -   R⁶ is selected from hydrogen, hydroxyl, alkyl, alkenyl, and        alkynyl; or R⁵ and R⁶ taken together form a cycloalkyl,        cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;    -   R⁷ is selected from —CHR⁸R⁹, —C₀₋₆alkyl-R¹⁰, —C₂₋₆alkenyl-R¹⁰,        and —C₂₋₆alkynyl-R¹⁰;    -   R⁸ is selected from —CO₂H, —CONH₂, —CONR¹⁶—CHR¹⁷—CONH₂,        —CONR¹⁶—CHR¹⁷—CO₂H, cycloalkyl, cycloalkenyl, aryl,        heterocyclyl, heteroaryl, —C₁₋₆alkylR¹⁰, —C₂₋₆alkenylR¹⁰ and        —C₂₋₆alkynylR¹⁰;    -   R⁹ is selected from hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H,        —C₀₋₆alkylCONH₂, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH,        —C₀₋₆alkylSC₁₋₆alkyl, —C₀₋₆alkylNHC(═NH)NH₂,        —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl, —C₀₋₆alkylheterocyclyl and        —C₀₋₆alkylheteroaryl;    -   R¹⁰ is selected from cycloalkyl, cycloalkenyl, aryl,        heterocyclyl and heteroaryl;    -   R¹¹ is selected from —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H, —C₀₋₆alkylCONH₂,        —C₀₋₆alkylNH₂, —C₀₋₆alkylSH, —C₀₋₆alkylSC₁₋₆alkyl,        —C₀₋₆alkylNHC(═NH)NH₂, —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl,        —C₀₋₆alkylheterocyclyl and —C₀₋₆alkylheteroaryl;    -   R¹² and R¹³ are independently selected from hydrogen, cyano,        nitro, halo, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₀₋₆alkylaryl,        —C₀₋₆alkylheteroaryl, —C₀₋₆alkylcycloalkyl,        —C₀₋₆alkylcycloalkenyl, —C₀₋₆alkylheterocyclyl, —O—R¹⁴,        —C(═O)—R¹⁴, —C(═O)—O—R¹⁴, —O—C(═O)—R¹⁴, —S(O)_(t)—R¹⁴, —N(R¹⁴)₂,        and —C(═O)—N(R¹⁴)₂, wherein each R¹⁴ is independently selected        from H, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylaryl,        —C₀₋₆alkylheteroaryl, —C₀₋₆alkylcycloalkyl,        —C₀₋₆alkylcycloalkenyl or —C₀₋₆alkylheterocyclyl;    -   t is 0-2;    -   R¹⁶ is selected from hydrogen, hydroxyl, alkyl, haloalkyl,        alkenyl, and alkynyl; and    -   R¹⁷ is selected from hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H,        —C₀₋₆alkylCONH₂, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH,        —C₀₋₆alkylSC₁₋₆alkyl, —C₀₋₆alkylNHC(═NH)NH₂,        —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl, —C₀₋₆alkylheterocyclyl and        —C₀₋₆alkylheteroaryl;    -   wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        aryl, heterocyclyl and heteroaryl are optionally substituted        with one or more optional substituents.

In one embodiment, the compound of formula (I) is a compound of formula(III) or a pharmaceutically acceptable salt thereof:

wherein

-   -   L and M are independently selected from N and CR¹³, provided        that both L and M are not N;    -   R² is selected from —C(═O)—NR³R⁴, —C(═S)—NR³R⁴, —CH₂—CHR⁵R⁶,        —CH═CR⁵R⁶, —C≡CR⁷, —CH₂—OR⁷, —C(═O)—OR⁷, —CH₂—NR³R⁴,        —CH₂—C(OH)R⁵R⁶, —CH(OH)—C(OH)R⁵R⁶, —C(═O)—NH—NR³R⁴,        —C(═O)—NH—OR⁷, —P(═O)(OH)—NR³R⁴, —NH—C(═O)—NR³R⁴,        —CH(CF₃)—NR³R⁴, and

-   -   Z is selected from —CH₂— or —NH—;    -   R³ is selected from —CHR⁸R¹¹, —C₂₋₆alkyl-R¹⁰, —C₂₋₆alkenyl-R¹⁰,        and —C₂₋₆alkynyl-R¹⁰;    -   R⁴ is selected from hydrogen, hydroxyl, alkyl, haloalkyl,        alkenyl, and alkynyl; or R³ and R⁴ taken together form a        heterocyclyl or heteroaryl ring;    -   R⁵ is selected from —CHR⁸R⁹, —C₀₋₆alkyl-R¹⁰, —C₂₋₆alkenyl-R¹⁰,        and —C₂₋₆alkynyl-R¹⁰;    -   R⁶ is selected from hydrogen, hydroxyl, alkyl, alkenyl, and        alkynyl; or R⁵ and R⁶ taken together form a cycloalkyl,        cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;    -   R⁷ is selected from —CHR⁸R⁹, —C₀₋₆alkyl-R¹⁰, —C₂₋₆alkenyl-R¹⁰,        and —C₂₋₆alkynyl-R¹⁰;    -   R⁸ is selected from —CO₂H, —CONH₂, —CONR¹⁶—CHR¹⁷—CONH₂,        —CONR¹⁶—CHR¹⁷—CO₂H, cycloalkyl, cycloalkenyl, aryl,        heterocyclyl, heteroaryl, —C₁₋₆alkylR¹⁰, —C₂₋₆alkenylR¹⁰ and        —C₂₋₆alkynylR¹⁰;    -   R⁹ is selected from hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H,        —C₀₋₆alkylCONH₂, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH,        —C₀₋₆alkylSC₁₋₆alkyl, —C₀₋₆alkylNHC(═NH)NH₂,        —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl, —C₀₋₆alkylheterocyclyl and        —C₀₋₆alkylheteroaryl;    -   R¹⁰ is selected from cycloalkyl, cycloalkenyl, aryl,        heterocyclyl and heteroaryl;    -   R¹¹ is selected from —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H, —C₀₋₆alkylCONH₂,        —C₀₋₆alkylNH₂, —C₀₋₆alkylSH, —C₀₋₆alkylSC₁₋₆alkyl,        —C₀₋₆alkylNHC(═NH)NH₂, —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl,        —C₀₋₆alkylheterocyclyl and —C₀₋₆alkylheteroaryl;    -   R¹² and R¹³ are independently selected from hydrogen, cyano,        nitro, halo, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₀₋₆alkylaryl, —C₀₋₆alkylheteroaryl, —C₀₋₆alkylcycloalkyl,        —C₀₋₆alkylcycloalkenyl, —C₀₋₆alkylheterocyclyl, —O—R¹⁴,        —C(═O)—R¹⁴, —C(═O)—O—R¹⁴, —O—C(═O)—R¹⁴, —S(O)_(t)—R¹⁴, —N(R¹⁴)₂,        and —C(═O)—N(R¹⁴)₂, wherein each R¹⁴ is independently selected        from H, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylaryl,        —C₀₋₆alkylheteroaryl, —C₀₋₆alkylcycloalkyl,        —C₀₋₆alkylcycloalkenyl or —C₀₋₆alkylheterocyclyl;    -   t is 0-2;    -   R¹⁶ is selected from hydrogen, hydroxyl, alkyl, haloalkyl,        alkenyl, and alkynyl; and    -   R¹⁷ is selected from hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H,        —C₀₋₆alkylCONH₂, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH,        —C₀₋₆alkylSC₁₋₆alkyl, —C₀₋₆alkylNHC(═NH)NH₂,        —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl, —C₀₋₆alkylheterocyclyl and        —C₀₋₆alkylheteroaryl;    -   wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        aryl, heterocyclyl and heteroaryl are optionally substituted        with one or more optional substituents.

In some embodiments of formula (I), (II) or (III), one or more of thefollowing applies:

-   -   X is

-   -    especially

-   -   Y is CH;    -   R¹ is optionally substituted thienyl, especially unsubstituted        thienyl or thienyl substituted with groups independently        selected from cyano, nitro, halo, —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —C₀₋₆alkylaryl, —C₀₋₆alkylheteroaryl,        —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylcycloalkenyl,        —C₀₋₆alkylheterocyclyl, —O—R¹⁴, —C(═O)—R¹⁴, —C(═O)—O—R¹⁴,        —O—C(═O)—R¹⁴, —S(O)_(t)—R¹⁴, —N(R¹⁴)₂, and —C(═O)—N(R¹⁴)₂,        wherein t is 0-2; especially unsubstituted thienyl or thienyl        substituted with cyano, nitro, halo, —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —C(═O)—R¹⁴, —C(═O)—O—R¹⁴, —O—C(═O)—R¹⁴, —N(R¹⁴)₂,        or —C(═O)—N(R¹⁴)₂; more especially unsubstituted thienyl or        thienyl substituted with —C(═O)—R¹⁴, —C(═O)—O—R¹⁴, —O—C(═O)—R¹⁴,        —N(R¹⁴)₂, or —C(═O)—N(R¹⁴)₂; most especially unsubstituted        thienyl;    -   each R¹⁴ is independently selected from H, —C₁₋₆alkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylaryl,        —C₀₋₆alkylheteroaryl, —C₀₋₆alkylcycloalkyl,        —C₀₋₆alkylcycloalkenyl or —C₀₋₆alkylheterocyclyl, especially H        or —C₁₋₆alkyl;    -   L and M are both CR¹³;    -   R¹² and R¹³ are independently selected from hydrogen cyano,        nitro, halo, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C(═O)—R¹⁴,        —C(═O)—O—R¹⁴, —O—C(═O)—R¹⁴, —N(R¹⁴)₂, and —C(═O)—N(R¹⁴)₂;        especially —C(═O)—R¹⁴, —C(═O)—O—R¹⁴, —O—C(═O)—R¹⁴, —N(R¹⁴)₂, and        —C(═O)—N(R¹⁴)₂; more especially hydrogen;    -   R¹² is hydrogen and L and M are both CH;    -   R² is selected from —C(═O)—NR³R⁴, —C(═S)—NR³R⁴, —CH═CR⁵R⁶,        —CH₂—OR⁷, —C(═O)—OR⁷, —CH₂—NR³R⁴, —C(═O)—NH—NR³R⁴,        —C(═O)—NH—OR⁷, —NH—C(═O)—NR³R⁴, —O—C(═O)—NR³R⁴ and        —CH(CF₃)—NR³R⁴, especially —C(═O)—NR³R⁴, —CH₂—OR⁷, —CH₂—NR³R⁴,        —NH—C(═O)—NR³R⁴, —CH═CR⁵R⁶ and —CH(CF₃)—NR³R⁴, more especially        —C(═O)—NR³R⁴ or —CH(CF₃)—NR³R⁴, most especially —C(═O)—NR³R⁴;    -   R³ is selected from —CHR⁸R⁹, —CHR⁸R¹¹ or —C₀₋₆alkyl-R¹⁰;        especially —CHR⁸R⁹, —CHR⁸R¹¹ or —C₁₋₆alkyl-R¹⁰; more especially        —CHR⁸R¹¹ or —C₂₋₆alkyl-R¹⁰; most especially —CHR⁸R¹¹;    -   R⁴ is hydrogen, alkyl, haloalkyl or perfluoroalkyl; especially        hydrogen;    -   R³ and R⁴ taken together form a heterocyclyl or heteroaryl ring;        especially where R³ and R⁴ form a monocyclic heterocyclyl or        heteroaryl ring which is substituted by a cycloalkyl,        cycloalkenyl, aryl, heterocyclyl or heteroaryl group, or where        R³ and R⁴ form a bicyclic heterocyclyl or heteroaryl ring, or        where R³ and R⁴ form a tricyclic spirane heterocyclyl group;        more especially R³ and R⁴ together form        1,2,3,4-tetrahydroisoquinolinyl,

which is optionally substituted at the ring nitrogen with a —SO₂Megroup, or piperidinyl which is substituted with benzimidazol-2-one or1,3-benzoxazin-2-one;

-   -   R⁵ is selected from —CHR⁸R⁹, —CHR⁸R¹¹ or —C₀₋₆alkyl-R¹⁰;        especially —CHR⁸R⁹, —CHR⁸R¹¹ or —C₁₋₆alkyl-R¹⁰; more especially        —CHR⁸R¹¹ or —C₂₋₆alkyl-R¹⁰; most especially —CHR⁸R¹¹;    -   R⁶ is hydrogen, alkyl or haloalkyl; especially hydrogen;    -   R⁵ and R⁶ taken together form a heterocyclyl or heteroaryl ring;    -   R⁷ is selected from —CHR⁸R⁹, —CHR⁸R¹¹ or —C₀₋₆alkyl-R¹⁰;        especially —CHR⁸R⁹, —CHR⁸R¹¹ or —C₁₋₆alkyl-R¹⁰; more especially        —CHR⁸R¹¹ or —C₂₋₆alkyl-R¹⁰; most especially —CHR⁸R¹¹;    -   R⁸ is selected from —CO₂H, —CONH₂, cycloalkyl, cycloalkenyl,        aryl, heterocyclyl, heteroaryl, —C₁₋₆alkylR¹⁰, —C₂₋₆alkenylR¹⁰        and —C₂₋₆alkynylR¹⁰; especially —CONH₂, aryl, heterocyclyl,        heteroaryl, —C₁₋₆alkylR¹⁰, —C₂₋₆alkenylR¹⁰ and —C₂₋₆alkynylR¹⁰;        more especially —CONH₂, aryl and —C₁₋₆alkylR¹⁰; more especially        —CONH₂ and aryl; most especially naphthyl, —CONH₂ and phenyl,    -   R⁹ is selected from —C₁₋₆alkyl, —C₁₋₆ perfluoroalkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H,        —C₀₋₆alkylCONH₂, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH,        —C₀₋₆alkylSC₁₋₆alkyl, —C₀₋₆alkylNHC(═NH)NH₂,        —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl, —C₀₋₆alkylheterocyclyl and        —C₀₋₆alkylheteroaryl; more especially —C₁₋₆alkyl, —C₁₋₆        perfluoroalkyl, —C₀₋₆alkylOH, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH,        —C₀₋₆alkylSC₁₋₆alkyl, —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl,        —C₀₋₆alkylheterocyclyl and —C₀₋₆alkylheteroaryl; more especially        —C₁₋₆alkyl, —C₁₋₆ perfluoroalkyl or —C₀₋₆alkylaryl; more        especially C₁alkylaryl, aryl, methyl or —CF₃; most especially        —CH₂-phenyl, phenyl, methyl or —CF₃;    -   R¹¹ is selected from —C₁₋₆alkyl, —C₁₋₆ perfluoroalkyl,        —C₀₋₆alkylOH, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH, —C₀₋₆alkylSC₁₋₆alkyl,        —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl, —C₀₋₆alkylheterocyclyl and        —C₀₋₆alkylheteroaryl; more especially —C₁₋₆alkyl, —C₁₋₆        perfluoroalkyl or —C₀₋₆alkylaryl; more especially C₁alkylaryl,        aryl, methyl or —CF₃; most especially —CH₂-phenyl, phenyl,        methyl or —CF₃;    -   R¹⁶ is selected from hydrogen, alkyl, haloalkyl or        perfluoroalkyl; especially hydrogen;    -   R¹⁷ is selected from hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,        —C₀₋₆alkylOH, —C₀₋₆alkylSH, —C₀₋₆alkylSC₁₋₆alkyl,        —C₀₋₆alkylcycloalkyl; more especially hydrogen, —C₁₋₆alkyl,        —C₁₋₆ perfluoroalkyl, —C₀₋₆alkylcycloalkyl; most especially        methyl or —CF₃;    -   wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        aryl, heterocyclyl and heteroaryl are optionally substituted        with one or more optional substituents.

In another aspect of the invention there is provided a use of a compoundof formula (I), (II) or (III) in the manufacture of a medicament for thetreatment or prevention of a disease or condition associated withinhibition of H-PGDS.

Reference herein to “treatment” and “prevention” is to be considered inits broadest context. The term “treatment” does not necessarily implythat a subject is treated until total recovery. Similarly, “prevention”does not necessarily mean that the subject will not eventually contracta disease or condition. Accordingly, “treatment” includes ameliorationof the symptoms of a particular disease or condition, or reducing theseverity of an existing disease, or condition. “Prevention” may beconsidered as reducing the likelihood of onset of a particular diseaseor condition or preventing or otherwise reducing the risk of developinga particular disease or condition.

An effective amount of a compound of formula (I) means an amountnecessary at least partly to attain the desired response, or to delaythe onset or inhibit progression or halt altogether, the onset orprogression of a particular disease or condition being treated. Theamount varies depending upon the health and physical condition of theindividual to be treated, the taxonomic group of individual to betreated, the degree of protection desired, the formulation of thecomposition, the assessment of the medical situation, and other relevantfactors. It is expected that the amount will fall in a relatively broadrange that can be determined through routine trials. An effective amountin relation to a human patient, for example, may lie in the range ofabout 0.1 ng per kg of body weight to 1 g per kg of body weight perdosage. In one embodiment, the dosage is in the range of 1 μg to 1 g perkg of body weight per dosage, such as in the range of 1 mg to 1 g per kgof body weight per dosage. In one embodiment, the dosage is in the rangeof 1 mg to 500 mg per kg of body weight per dosage. In anotherembodiment, the dosage is in the range of 1 mg to 250 mg per kg of bodyweight per dosage. In yet another embodiment, the dosage is in the rangeof 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mgper kg of body weight per dosage. In yet another embodiment, the dosageis in the range of 1 μg to 1 mg per kg of body weight per dosage. Dosageregimes may be adjusted to provide the optimum therapeutic response. Forexample, several divided doses may be administered daily, weekly,monthly or other suitable time intervals, or the dose may beproportionally reduced as indicated by the exigencies of the situation.

The term “subject” as used herein includes mammals, humans, primates,livestock animals (eg. sheep, pigs, cattle, horses, donkeys), laboratorytest animals (eg. mice, rabbits, rats, guinea pigs), companion animals(eg. dogs, cats) and captive wild animals (eg. foxes, kangaroos, deer).In some embodiments, the subject is human or a laboratory test animal,especially a human.

As used herein, “an H-PGDS associated disease or condition” is a diseaseor condition which benefits from the inhibition of H-PGDS. For example,such diseases or conditions are those in which H-PGDS is inappropriatelystimulated or overactive. H-PGDS associated diseases or conditionsinclude allergies, inflammation, pain, bronchoconstriction, musclenecrosis, cancer, arthritis, irritable bowel diseases, irritable bowelsyndrome, skin inflammation and irritation, and cardiovascular diseasesor conditions. In one embodiment, the H-PGDS associated diseases orconditions are selected from cancer, rheumatoid arthritis, Crohn'sdisease, ulcerative colitis, painful diabetic neuropathy, postherpeticneuralgia, eczema, psoriasis, chronic pain, chronic inflammation,neuropathic pain conditions, niacin-induced skin flushing and celiactype disease (for example resulting from lactose intolerance), carpaltunnel syndrome, back pain, headache, cancer pain, arthritic pain,chronic post-surgical pain, allergic conjunctivitis, atopic dermatitis,neuroinflammation, allergic rhinitis, nasal congestion, rhinorrhea,perennial rhinitis, nasal inflammation, asthma, chronic obstructivepulmonary disease (COPD), chronic or acute bronchoconstriction, chronicbronchitis, small airways obstruction, emphysema, chronic eosinophilicpneumonia, adult respiratory distress syndrome, airways disease that isassociated with pulmonary hypertension, acute lung injury,bronchiectasis, sinusitis, allergic conjunctivitis, atopic dermatitis,and airways eosinophilia, obstruction, hypersensitivity orhypersecretion. In one embodiment, these diseases or conditions includeallergies, inflammation and chronic pain conditions. For example, in oneembodiment, the disease or condition is asthma, allergic conjunctivitis,atopic dermatitis, allergic rhinitis, neuroinflammation, chronicobstructive pulmonary disease or airways eosinophilia, obstruction,hypersensitivity or hypersecretion.

In some embodiments, compounds of the invention advantageously displayselectivity for H-PGDS over other prostaglandin synthases. Thisadvantageously may provide compounds that provide fewer side effectsthan other pharmaceuticals that target prostaglandin production.

In a further aspect of the invention there is provided a method ofinhibiting H-PGDS, comprising contacting H-PGDS with a compound offormula (I). It should be understood that the method in this aspect ofthe invention relates to H-PGDS which may be located in vitro or invivo, especially in vitro. This method includes, but is not limited to,screening of compound libraries to identify compounds that bind toH-PGDS, assays to determine the biological activity of compounds thatbind to H-PGDS, experiments to develop a pharmacophore of H-PGDS orexperiments to investigate the physiology or pharmacology of H-PGDS.

The present invention further contemplates a combination of therapies,such as the administration to a subject of the compounds of theinvention or pharmaceutically acceptable salts or prodrugs thereof,together with other agents or procedures which are useful in thetreatment or prevention of diseases and conditions in respect of whichinhibition of H-PGDS is associated with effective treatment.

The compounds of formula (I), (II) or (III) or pharmaceuticallyacceptable salts or prodrugs thereof may also be administered incombination with other agents or procedures which are useful in thetreatment or prevention of H-PGDS associated diseases or conditions. Forexample, other agents that may be used with compounds of formula (I),(II) or (III) include anti-inflammatories such as corticosteroids (forexample, fluticasone, budesonide and mometasone), especially oral orintranasal anti-inflammatories; bronchodilators such as anticholinergics(for example, tiotropium bromide and ipratropin) and β₂ agonists (forexample, salmeterol, salbutamol, camoterol, indacaterol and formaterol);methylxanthines such as theophylline; and biologics, such as monoclonalantibodies (for example antibodies against TNFa and immunoglobulins (egIgE), including omalizumab). Such combinations may be useful in thetreatment of asthma and chronic obstructive pulmonary disease.

Similarly anti-inflammatories such as corticosteroids (for example,fluticasone, budesonide and mometasone), especially oral or intranasalanti-inflammatories; anti-histamines, such as H1-receptor antagonists;oral or intranasal decongestants; and allergan immunotherapy usingrecombinant allergans such as different types of pollen may be used withcompounds of formula (I), (II) and (III), especially for the treatmentof allergic rhinitis.

Other agents that may be used with compounds of formula (I), (II) and(III) include glucocorticosteroids or dissociated agonists of thecorticoid receptor; β₂ agonists including long acting β₂ agonists;muscarinic M3 receptor antagonists or anticholinergic agents; histaminereceptor antagonists including H1 or H3 antagonists; 5-lypoxygenaseinhibitors; thromboxane inhibitors; 5-lipoxygenase activating protein(FLAP) antagonists; leukotriene antagonists including antagonists ofLTB₄, LTC₄, LTD₄ and LTE₄; α₁- and α₂-adrenoceptor agonistvasoconstrictor sympathomimetic agents for decongestant use; PDEinhibitors including PDE3, PDE4 and PDE5 inhibitors such astheophylline; sodium cromoglycate; monoclonal antibodies active againstendogenous inflammatory entities; integrin antagonists; adhesionmolecule inhibitors such as VLA-4 antagonists; kinin-B₁- or B₂-receptorantagonists; immunosuppressive agents, including inhibitors of the IgEpathway and cyclosporin; inhibitors of matrix metalloproteases (MMPs)such as MMP9 and MMP12; tachykinin NK1, NK2 or NK3 receptor antagonists;protease inhibitors such as elastase inhibitors, chymase and cathepsinG; adenosine Ata receptor agonists and A2b antagonists; inhibitors ofurokinase; compounds that act on dopamine receptors such as D2 agonists;modulators of the NFκB pathway such as IKK inhibitors; modulators ofcytokine signalling pathways such as syk kinase, JAK kinase, p38 kinase,SPHK-1 kinase, Rho kinase, EGF-R or MK-2; agents that can be classed asmucolytics or anti-tussive, and mucokinetics; antibiotics; antivirals;vaccines; chemokines; epithelial sodium channel (ENaC) blockers orepithelial sodium channel (ENaC) inhibitors; P2Y2 agonists and othernucleotide receptor agonists; niacin; and adhesion factors includingVLAM, ICAM and ELAM.

In another aspect the present invention relates to a compound of formula(II):

wherein

-   -   Y is —N— or —CH—;    -   L and M are independently selected from N and CR¹³, provided        that both L and M are not N;    -   R² is selected from —C(═O)—NR³R⁴, —C(═S)—NR³R⁴, —CH₂—CHR⁵R⁶,        —CH═CR⁵R⁶, —C≡CR⁷, —CH₂—OR⁷, —C(═O)—OR⁷, —CH₂—NR³R⁴,        —CH₂—C(OH)R⁵R⁶, —CH(OH)—C(OH)R⁵R⁶, —C(═O)—NH—NR³R⁴,        —C(═O)—NH—OR⁷, —P(═O)(OH)—NR³R⁴, —NH—C(═O)—NR³R⁴,        —O—C(═O)—NR³R⁴, —CH(CF₃)—NR³R⁴, and

-   -   Z is selected from —CH₂— or —NH—;    -   R³ is selected from —CHR⁸R¹¹, —C₂₋₆alkyl-R¹⁰, —C₂₋₆alkenyl-R¹⁰,        and —C₂₋₆alkynyl-R¹⁰;    -   R⁴ is selected from hydrogen, hydroxyl, alkyl, haloalkyl,        alkenyl, and alkynyl; or R³ and R⁴ taken together form a        heterocyclyl or heteroaryl ring;    -   R⁵ is selected from —CHR⁸R⁹, —C₀₋₆alkyl-R¹⁰, —C₂₋₆alkenyl-R¹⁰,        and —C₂₋₆alkynyl-R¹⁰;    -   R⁶ is selected from hydrogen, hydroxyl, alkyl, alkenyl, and        alkynyl; or R⁵ and R⁶ taken together form a cycloalkyl,        cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;    -   R⁷ is selected from —CHR⁸R⁹, —C₀₋₆alkyl-R¹⁰, —C₂₋₆alkenyl-R¹⁰,        and —C₂₋₆alkynyl-R¹⁰;    -   R⁸ is selected from —CO₂H, —CONH₂, —CONR¹⁶—CHR¹⁷—CONH₂,        —CONR¹⁶—CHR¹⁷—CO₂H, cycloalkyl, cycloalkenyl, aryl,        heterocyclyl, heteroaryl, —C₁₋₆alkylR¹⁰, —C₂₋₆alkenylR¹⁰ and        —C₂₋₆alkynylR¹⁰;    -   R⁹ is selected from hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H,        —C₀₋₆alkylCONH₂, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH,        —C₀₋₆alkylSC₁₋₆alkyl, —C₀₋₆alkylNHC(═NH)NH₂,        —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl, —C₀₋₆alkylheterocyclyl and        —C₀₋₆alkylheteroaryl;    -   R¹⁰ is selected from cycloalkyl, cycloalkenyl, aryl,        heterocyclyl and heteroaryl;    -   R¹¹ is selected from —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H, —C₀₋₆alkylCONH₂,        —C₀₋₆alkylNH₂, —C₀₋₆alkylSH, —C₀₋₆alkylSC₁₋₆alkyl,        —C₀₋₆alkylNHC(═NH)NH₂, —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl,        —C₀₋₆alkylheterocyclyl and —C₀₋₆alkylheteroaryl;    -   R¹² and R¹³ are independently selected from hydrogen, cyano,        nitro, halo, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₀₋₆alkylaryl, —C₀₋₆alkylheteroaryl, —C₀₋₆alkylcycloalkyl,        —C₀₋₆alkylcycloalkenyl, —C₀₋₆alkylheterocyclyl, —O—R¹⁴,        —C(═O)—R¹⁴, —C(═O)—O—R¹⁴, —O—C(═O)—R¹⁴, —S(O)_(t)—R¹⁴, —N(R¹⁴)₂,        and —C(═O)—N(R¹⁴)₂, wherein each R¹⁴ is independently selected        from H, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylaryl,        —C₀₋₆alkylheteroaryl, —C₀₋₆alkylcycloalkyl,        —C₀₋₆alkylcycloalkenyl or —C₀₋₆alkylheterocyclyl;    -   t is 0-2;    -   R¹⁶ is selected from hydrogen, hydroxyl, alkyl, haloalkyl,        alkenyl, and alkynyl; and    -   R¹⁷ is selected from hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H,        —C₀₋₆alkylCONH₂, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH,        —C₀₋₆alkylSC₁₋₆alkyl, —C₀₋₆alkylNHC(═NH)NH₂,        —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl, —C₀₋₆alkylheterocyclyl and        C₀₋₆alkylheteroaryl;    -   wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        aryl, heterocyclyl and heteroaryl are optionally substituted        with one or more optional substituents;        or a salt thereof;        with the provisos that when:    -   (i) Y is —CH—, R² is —C(═O)—NR³R⁴, R³ and R⁴ taken together form        4-(2-pyrimidinyl)-1-piperazinyl, L is CH and M is CR¹³, then R¹³        is not hydrogen when R¹² is methyl, and R¹² is not hydrogen when        R¹³ is methyl;    -   (ii) Y is CH—, R² is —C(═O)—NR³R⁴, R¹² is hydrogen, L is CH and        M is CH, then R³ and R⁴ taken together do not form        5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl,        2-(1-pyrrolidinylmethyl)-1-pyrrolidinyl or        2-methyl-1-pyrrolidinyl; and    -   (iii) Y is —CH—, R² is —C(═O)—NR³R⁴, R³ is        4-[4-(5,6,7,8-tetrahydro-1-methoxy-2-naphthalenyl)-1-piperidinyl]butyl,        R⁴ is hydrogen, and L and M are CH, then R¹² is not cyano or        chloro.

In another aspect the present invention relates to a compound of formula(III):

wherein

-   -   L and M are independently selected from N and CR¹³, provided        that both L and M are not N;    -   R² is selected from —C(═O)—NR³R⁴, —C(═S)—NR³R⁴, —CH₂—CHR⁵R⁶,        —CH═CR⁵R⁶, —C≡CR⁷, —CH₂—OR⁷, —C(═O)—OR⁷, —CH₂—NR³R⁴,        —CH₂—C(OH)R⁵R⁶, —CH(OH)—C(OH)R⁵R⁶, —C(═O)—NH—NR³R⁴,        —C(═O)—NH—OR⁷, —P(═O)(OH)—NR³R⁴, —NH—C(═O)—NR³R⁴,        —O—C(═O)—NR³R⁴, —CH(CF₃)—NR³R⁴, and

-   -   Z is selected from —CH₂— or —NH—;    -   R³ is selected from —CHR⁸R¹¹, —C₂₋₆alkyl-R¹⁰, —C₂₋₆alkenyl-R¹⁰,        and —C₂₋₆alkynyl-R¹⁰;    -   R⁴ is selected from hydrogen, hydroxyl, alkyl, haloalkyl,        alkenyl, and alkynyl; or R³ and R⁴ taken together form a        heterocyclyl or heteroaryl ring;    -   R⁵ is selected from —CHR⁸R⁹, —C₂₋₆alkenyl-R¹⁰, and        C₂₋₆alkynyl-R¹⁰;    -   R⁶ is selected from hydrogen, hydroxyl, alkyl, alkenyl, and        alkynyl; or R⁵ and R⁶ taken together form a cycloalkyl,        cycloalkenyl, aryl, heterocyclyl or heteroaryl ring;    -   R⁷ is selected from —CHR⁸R⁹, —C₀₋₆alkyl-R¹⁰, —C₂₋₆alkenyl-R¹⁰,        and —C₂₋₆alkynyl-R¹⁰;    -   R⁸ is selected from —CO₂H, —CONH₂, —CONR¹⁶—CHR¹⁷—CONH₂,        —CONR¹⁶—CHR¹⁷—CO₂H, cycloalkyl, cycloalkenyl, aryl,        heterocyclyl, heteroaryl, —C₁₋₆alkylR¹⁰, —C₂₋₆alkenylR¹⁰ and        —C₂₋₆alkynylR¹⁰;    -   R⁹ is selected from hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H,        —C₀₋₆alkylCONH₂, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH,        —C₀₋₆alkylSC₁₋₆alkyl, —C₀₋₆alkylNHC(═NH)NH₂,        —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl, —C₀₋₆alkylheterocyclyl and        —C₀₋₆alkylheteroaryl;    -   R¹⁰ is selected from cycloalkyl, cycloalkenyl, aryl,        heterocyclyl and heteroaryl;    -   R¹¹ is selected from —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H, —C₀₋₆alkylCONH₂,        —C₀₋₆alkylNH₂, —C₀₋₆alkylSH, —C₀₋₆alkylSC₁₋₆alkyl,        —C₀₋₆alkylNHC(═NH)NH₂, —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl,        —C₀₋₆alkylheterocyclyl and —C₀₋₆alkylheteroaryl;    -   R¹² and R¹³ are independently selected from hydrogen, cyano,        nitro, halo, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₀₋₆alkylaryl, —C₀₋₆alkylheteroaryl, —C₀₋₆alkylcycloalkyl,        —C₀₋₆alkylcycloalkenyl, —C₀₋₆alkylheterocyclyl, —O—R¹⁴,        —C(═O)—R¹⁴, —C(═O)—O—R¹⁴, —O—C(═O)—R¹⁴, —S(O)_(t)—R¹⁴, —N(R¹⁴)₂,        and —C(═O)—N(R¹⁴)₂, wherein each R¹⁴ is independently selected        from H, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylaryl,        —C₀₋₆alkylheteroaryl, —C₀₋₆alkylcycloalkyl,        —C₀₋₆alkylcycloalkenyl or —C₀₋₆alkylheterocyclyl;    -   t is 0-2;    -   R¹⁶ is selected from hydrogen, hydroxyl, alkyl, haloalkyl,        alkenyl, and alkynyl; and    -   R¹⁷ is selected from hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H,        —C₀₋₆alkylCONH₂, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH,        —C₀₋₆alkylSC₁₋₆alkyl, —C₀₋₆alkylNHC(═NH)NH₂,        —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl, —C₀₋₆alkylheterocyclyl and        —C₀₋₆alkylheteroaryl;    -   wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        aryl, heterocyclyl and heteroaryl are optionally substituted        with one or more optional substituents;        or a salt thereof;        with the provisos that when:    -   (i) R² is —C(═O)—NR³R⁴, R³ and R⁴ taken together form        4-(2-pyrimidinyl)-1-piperazinyl, L is CH and M is CR¹³, then R¹³        is not hydrogen when R¹² is methyl, and R¹² is not hydrogen when        R¹³ is methyl;    -   (ii) R² is —C(═O)—NR³R⁴, R¹² is hydrogen, L is CH and M is CH,        then R³ and R⁴ taken together do not form        5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl,        2-(1-pyrrolidinylmethyl)-1-pyrrolidinyl or        2-methyl-1-pyrrolidinyl; and    -   (iii) R² is —C(═O)—NR³R⁴, R³ is        4-[4-(5,6,7,8-tetrahydro-1-methoxy-2-naphthalenyl)-1-piperidinyl]butyl,        R⁴ is hydrogen, and L and M are CH, then R¹² is not cyano or        chloro.

In some embodiments of formula (II) or (III), one or more of thefollowing applies:

-   -   Y is —CH—;    -   L and M are both CR¹³;    -   R¹² and R¹³ are independently selected from hydrogen cyano,        nitro, halo, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C(═O)—R¹⁴,        —C(═O)—O—R¹⁴, —O—C(═O)—R¹⁴, —N(R¹⁴)₂, and —C(═O)—N(R)₂;        especially —C(═O)—R¹⁴, —C(═O)—O—R¹⁴, —O—C(═O)—R¹⁴, —N(R¹⁴)₂, and        —C(═O)—N(R¹⁴)₂; more especially hydrogen;    -   each R¹⁴ is independently selected from H or —C₁₋₆alkyl;    -   R¹² is hydrogen and L and M are both CH;    -   R² is selected from —C(═O)—NR³R⁴, —C(═S)—NR³R⁴, —CH═CR⁵R⁶,        —CH₂—OR⁷, —C(═O)—OR⁷, —CH₂—NR³R⁴, —C(═O)—NH—NR³R⁴,        —C(═O)—NH—OR⁷, —NH—C(═O)—NR³R⁴, —O—C(═O)—NR³R⁴ and        —CH(CF₃)—NR³R⁴, especially —C(═O)—NR³R⁴, —CH₂—OR⁷, —CH₂—NR³R⁴,        —NH—C(═O)—NR³R⁴, —CH═CR⁵R⁶ and —CH(CF₃)—NR³R⁴, more especially        —C(═O)—NR³R⁴ or —CH(CF₃)—NR³R⁴, most especially —C(═O)—NR³R⁴;    -   R³ is selected from —CHR⁸R¹¹ or —C₂₋₆alkyl-R¹⁰; most especially        —CHR⁸R¹¹;    -   R⁴ is hydrogen, alkyl, haloalkyl or perfluoroalkyl; especially        hydrogen;    -   R³ and R⁴ taken together form a heterocyclyl or heteroaryl ring;        especially where R³ and R⁴ form a monocyclic heterocyclyl or        heteroaryl ring which is substituted by a cycloalkyl,        cycloalkenyl, aryl, heterocyclyl or heteroaryl group, or where        R³ and R⁴ form a bicyclic heterocyclyl or heteroaryl ring, or        where R³ and R⁴ form a tricyclic spirane heterocyclyl group;        more especially where R³ and R⁴ together form        1,2,3,4-tetrahydroisoquinolinyl,

which is optionally substituted at the ring nitrogen with a SO₂Me group,or piperidinyl which is substituted with benzimidazol-2-one or1,3-benzoxazin-2-one;

-   -   R⁵ is selected from —CHR⁸R⁹, —CHR⁸R¹¹ or —C₀₋₆alkyl-R¹⁰;        especially CHR⁸R⁹, —CHR⁸R¹¹ or —C₁₋₆alkyl-R¹⁰; more especially        —CHR⁸R¹¹ or —C₂₋₆alkyl-R¹⁰; most especially —CHR⁸R¹¹;    -   R⁶ is hydrogen, alkyl or haloalkyl; especially hydrogen;    -   R⁵ and R⁶ taken together form a heterocyclyl or heteroaryl ring;    -   R⁷ is selected from —CHR⁸R⁹, —CHR⁸R¹¹ and —C₀₋₆alkyl-R¹⁰;        especially —CHR⁸R⁹, —CHR⁸R¹¹ and —C₁₋₆alkyl-R¹⁰; more especially        —CHR⁸R¹¹ and —C₂₋₆alkyl-R¹⁰; most especially —CHR⁸R¹¹;    -   R⁸ is selected from —CO₂H, —CONH₂, cycloalkyl, cycloalkenyl,        aryl, heterocyclyl, heteroaryl, —C₁₋₆alkylR¹⁰, —C₂₋₆alkenylR¹⁰        and —C₂₋₆alkynylR¹⁰; especially —CONH₂, aryl, heterocyclyl,        heteroaryl, —C₁₋₆alkylR¹⁰, —C₂₋₆alkenylR¹⁰ and —C₂₋₆alkynylR¹⁰;        more especially —CONH₂, aryl and —C₁₋₆alkylR¹⁰; more especially        —CONH₂ and aryl; most especially napthyl, —CONH₂ and phenyl,    -   R⁹ is selected from —C₁₋₆alkyl, —C₁₋₆perfluoroalkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylOH, —C₀₋₆alkylCO₂H,        —C₀₋₆alkylCONH₂, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH,        —C₀₋₆alkylSC₁₋₆alkyl, —C₀₋₆alkylNHC(═NH)NH₂,        —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl, —C₀₋₆alkylheterocyclyl and        —C₀₋₆alkylheteroaryl; more especially —C₁₋₆alkyl, —C₁₋₆        perfluoroalkyl, —C₀₋₆alkylOH, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH,        —C₀₋₆alkylSC₁₋₆alkyl, —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl,        —C₀₋₆alkylheterocyclyl and —C₀₋₆alkylheteroaryl; more especially        —C₁₋₆alkyl, —C₁₋₆ perfluoroalkyl or —C₀₋₆alkylaryl; more        especially C₁alkylaryl, aryl, methyl or —CF₃; most especially        —CH₂-phenyl, phenyl, methyl or —CF₃;    -   R¹¹ is selected from —C₁₋₆alkyl, —C₁₋₆ perfluoroalkyl,        —C₀₋₆alkylOH, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH, —C₀₋₆alkylSC₁₋₆alkyl,        —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylaryl, —C₀₋₆alkylheterocyclyl and        —C₀₋₆alkylheteroaryl; more especially —C₁₋₆alkyl,        —C₁₋₆perfluoroalkyl or —C₀₋₆alkylaryl; more especially        C₁alkylaryl, aryl, methyl or —CF₃; most especially —CH₂-phenyl,        phenyl, methyl or —CF₃;    -   R¹⁶ is selected from hydrogen, alkyl, haloalkyl or        perfluoroalkyl; especially hydrogen;    -   R¹⁷ is selected from hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,        —C₀₋₆alkylOH, —C₀₋₆alkylSH, —C₀₋₆alkylSC₁₋₆alkyl,        —C₀₋₆alkylcycloalkyl; more especially hydrogen, —C₁₋₆alkyl,        —C₁₋₆perfluoroalkyl, —C₀₋₆alkylcycloalkyl; most especially        methyl or —CF₃;    -   wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        aryl, heterocyclyl and heteroaryl are optionally substituted        with one or more optional substituents.

As used herein, the term “alkyl” refers to a straight chain or branchedsaturated hydrocarbon group having 1 to 12 carbon atoms. Whereappropriate, the alkyl group may have a specified number of carbonatoms, for example, —C₁₋₆alkyl which includes alkyl groups having 1, 2,3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. Examplesof suitable alkyl groups include, but are not limited to, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, 2-methylbutyl,3-methylbutyl, 4-methylbutyl, n-hexyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 5-methylpentyl, 2-ethylbutyl, 3-ethylbutyl, heptyl,octyl, nonyl, decyl, undecyl and dodecyl.

As used herein, the term “alkenyl” refers to a straight-chain orbranched hydrocarbon group having one or more double bonds betweencarbon atoms and having 2 to 12 carbon atoms. Where appropriate, thealkenyl group may have a specified number of carbon atoms. For example,—C₂-C₆ as in “C₂-C₆alkenyl” includes groups having 2, 3, 4, 5 or 6carbon atoms in a linear or branched arrangement. Examples of suitablealkenyl groups include, but are not limited to, ethenyl, propenyl,isopropenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl,hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl anddodecenyl.

As used herein, the term “alkynyl” refers to a straight-chain orbranched hydrocarbon group having one or more triple bonds betweencarbon atoms and having 2 to 12 carbon atoms. Where appropriate, thealkynyl group may have a specified number of carbon atoms. For example,—C₂-C₆ as in “C₂-C₆alkynyl” includes groups having 2, 3, 4, 5 or 6carbon atoms in a linear or branched arrangement. Examples of suitablealkynyl groups include, but are not limited to, ethynyl, propynyl,butynyl, pentynyl, hexynyl, octynyl, nonynyl, decynyl, undecynyl anddodecynyl.

As used herein, the term “cycloalkyl” refers to a saturated cyclichydrocarbon. The cycloalkyl ring may include a specified number ofcarbon atoms. For example, a 3 to 8 membered cycloalkyl group includes3, 4, 5, 6, 7 or 8 carbon atoms. The cycloalkyl group may also comprisetwo or three rings in which at least one ring is a cycloalkyl group.When there are two or three rings, each ring is linked to one or more ofthe other rings by sharing one or more ring atoms forming a spirane orfused ring system. The cycloalkyl group also include a carbonyl groupattached to a ring carbon atom. Examples of suitable cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentanyl,cyclohexanyl, cycloheptanyl, cyclooctanyl, decahydronaphthalyl,bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.1]heptanyl,bicyclo[2.2.1]heptanyl, adamantanyl and spiranes such asspiro[4.5]decane.

As used herein, the term “cycloalkenyl” refers to a cyclic hydrocarbonhaving at least one double bond, which is not aromatic. The cycloalkenylring may include a specified number of carbon atoms. For example, a 4 to8 membered cycloalkenyl group contains at least one double bond and 4,5, 6, 7 or 8 carbon atoms. The cycloalkenyl group may also comprise twoor three rings, provided that at least one ring is a cycloalkenyl ring.When there are two or three rings, each ring is linked to one or more ofthe other rings by sharing one or more ring atoms forming a spirane orfused ring system. The cycloalkenyl group may also include a carbonylgroup attached to an unsaturated ring carbon atom. Examples of suitablecycloalkenyl groups include, but are not limited to cyclopentenyl,cyclopenta-1,3-dienyl, cyclohexenyl, cyclohexen-1,3-dienyl andcyclohexen-1,4-dienyl.

As used herein, the term “aryl” is intended to mean any stable,monocyclic, bicyclic or tricyclic carbon ring of up to 7 atoms in eachring, wherein at least one ring is aromatic. When more than one ring ispresent, the rings may be fused to one another. Examples of aryl groupsinclude, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl, biphenyl, binaphthyl, anthracenyl, phenanthrenyl, phenalenyland fluorenyl.

The term “heterocyclic” or “heterocyclyl” as used herein, refers to acycloalkyl or cycloalkenyl group in which one or more carbon atoms havebeen replaced by heteroatoms independently selected from N, S and O. Forexample, between 1 and 4 carbon atoms in each ring may be replaced byheteroatoms independently selected from N, S and O. The heterocyclicgroup may be monocyclic, bicyclic or tricyclic in which at least onering is heterocyclic. When there are two or three rings, each ring islinked to one or more of the other rings by sharing one or more ringatoms forming a spirane or fused ring system. The heterocyclyl group mayalso include a carbonyl group attached to an unsaturated ring carbon.Examples of suitable heterocyclyl groups include tetrahydrofuranyl,tetrahydrothiophenyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,dithiolyl, 1,3-dioxolanyl, pyrazolinyl, imidazolinyl, imidazolidinyl,1,4-dioxanyl, 1,3-dioxanyl, dioxinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, pyranyl, 1,4-dithiane, 1,3,5-trithiane,quinuclidine and tetrahydropyranyl.

The term “heteroaryl” as used herein, represents a stable monocyclic,bicyclic or tricyclic ring of up to 7 atoms in each ring, wherein atleast one ring is aromatic and at least one ring contains from 1 to 4heteroatoms selected from the group consisting of O, N and S. When morethan one ring is present the rings may be fused. The heteroaryl groupmay also include a carbonyl group attached to an unsaturated carbon inthe ring system. Examples of suitable heteroaryl groups includepyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl,1,2,3-triazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl,oxadiazolyl, oxatriazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, azepinyl, oxepinyl, thiepinyl, diazepinyl,coumaranyl, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl,indolinyl, isoindolyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, 1-benzopyranyl, 2-benzopyranyl,benzopyran-2-on-yl, benzopyran-1-on-yl, quinolinyl,tetrahydroquinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl,quinoxalinyl, tetrahydroquinoxalinyl, naphthyridinyl, acridinyl,carbazolyl, xanthenyl, phenazinyl, phenothiazinyl, phenoxazinyl,1,4-benzodiazepin-2-on-yl, 1,5-benzodiazepin-2-on-yl,1,4-benzodiazepin-2,5-dion-yl,pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dion-yl,1,4-benzothiazepin-5-on-yl,5,11-dihydro-benzo[e]pyrido[3,2-b][1,4]-diazepin-6-on-yl, chromonyl,pyranocoumarinyl, 3,4-dihydroquinoxalin-2-on-yl, quinazolinonyl,quinazolindionyl, imidazoquinoxalinyl,2,3-dihydrospiro[indene-1,4′-piperidine] andspiro[indoline-3,4′-piperidine].

The cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl group mayadvantageously be a privileged substructure or form part of a privilegedsubstructure. Privileged substructures are molecular frameworks able toprovide ligands for diverse receptors. Examples of privilegedsubstructures include biphenyl, arylpiperidine, arylpiperazine,aryl-1,4-dihydropyridine, aryl-dihydropyrimidone,1,4-benzodiazepin-2-one, 1,5-benzodiazepin-2-one,1,4-benzodiazepin-2,5-dione,pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione, 1,4-benzothiazepin-5-one,5,11-dihydro-benzo[e]pyrido[3,2-b][1,4]-diazepin-6-one, benzopyran,chromone, coumarin, pyranocoumarin, 3,4-dihydroquinoxalin-2-one,quinazolinone, quinazolindione, imidazoquinoxaline, indole,benzimidazole, benzofuran and benzothiophene. Other privilegedsubstructures would be known to a person skilled in the art. Theprivileged substructure may be optionally substituted.

Unless otherwise defined, the term “optionally substituted” means, forexample, that each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,aryl, heterocyclyl and heteroaryl (including thienyl and thiazolyl),whether an individual entity or as part of a larger entity, may beoptionally substituted with one or more optional substituents selectedfrom R¹⁵, R¹⁵—O—(CH₂)_(q)—, R¹⁵—S—(CH₂)_(q)—, hydroxyl(CH₂)_(q)—,HS—(CH₂)_(q)—, R¹⁵—C(═O)—O—(CH₂)_(q)—, R¹⁵—O—C(═O)—(CH₂)_(q)—,R¹⁵—C(═O)—(CH₂)_(q)—, (R¹⁵)₂N—C(═O)—(CH₂)_(q)—, R¹⁵S(O)_(j)—(CH₂)_(q)—,(R¹⁵)₂N—(CH₂)_(q)—, cyano, nitro and halo, wherein each R¹⁵ isindependently selected from H, alkyl, alkenyl, alkynyl, —(CH₂)_(i)-aryl,—(CH₂)_(i)-heteroaryl, —(CH₂)_(i)-cycloalkyl, —(CH₂)_(i)-cycloalkenyl or—(CH₂)_(i)-heterocyclyl; q and i are 0 or an integer from 1 to 6, and jis 0 or an integer of 1 or 2. Furthermore, the alkyl, alkenyl, alkynyl,aryl, heteroaryl, cycloalkyl, cycloalkenyl and heterocyclyl groupswithin the optional substituents may be further optionally substitutedwith one or more substituents selected from cyano, hydroxyl, nitro,halo, alkyl, haloalkyl, alkenyl, alkynyl or alkoxyl groups.

In one embodiment, the optional substituents include fluoro, chloro,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, hydroxy, methoxy,ethoxy, propoxy, isopropoxy, hydroxymethyl, trifluoromethyl,trifluoromethoxy, cyano, nitro, acetyl, amino, methylamino,dimethylamino, —CO—NH₂, —CO₂H, —COCH₃, —SO₂CH₃, benzimidazol-2-one,1,3-benzoxazin-2-one, tetrazole, piperidinyl, piperazinyl,1,4-dihydropyridinyl, dihydropyrimidonyl, phenyl and benzyl in which thephenyl or benzyl ring is optionally substituted with halo, methyl,methoxy, phenyl, tetrazole, piperidinyl, piperazinyl,1,4-dihydropyridinyl or dihydropyrimidonyl; especially hydroxy, amino,hydroxymethyl, phenyl, cyano, —CO—NH₂, —CO₂H, —COCH₃, benzimidazol-2-oneand 1,3-benzoxazin-2-one.

As used herein, the term “halogen” or “halo” refers to fluorine(fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo).

As used herein, the term “haloalkyl” refers to an alkyl group (asdefined above) in which one or more hydrogen atoms are replaced withhalogen atoms. “Haloalkyl” includes perhaloalkyl groups in which allhydrogen atoms are replaced with halogen atoms. Examples of haloalkylgroups include fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, bromomethyl,dibromomethyl, iodomethyl, diiodomethyl, 1-fluoroethyl, 2-fluoroethyl,1,2-difluoroethyl, 1-chloroethyl, 2-chloroethyl, 1,2-dichloroethyl.Perhaloalkyl groups include perfluoroalkyl groups such astrifluoromethyl and pentafluoroethyl and perchloroalkyl groups such astrichloromethyl and pentachloromethyl.

The compounds of the invention may be in the form of pharmaceuticallyacceptable salts. It will be appreciated however thatnon-pharmaceutically acceptable salts also fall within the scope of theinvention since these may be useful as intermediates in the preparationof pharmaceutically acceptable salts or may be useful during storage ortransport. Suitable pharmaceutically acceptable salts include, but arenot limited to, salts of pharmaceutically acceptable inorganic acidssuch as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric,sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptableorganic acids such as acetic, propionic, butyric, tartaric, maleic,hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic,benzoic, succinic, oxalic, phenylacetic, methanesulphonic,toluenesulphonic, benezenesulphonic, salicyclic sulphanilic, aspartic,glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic,ascorbic and valeric acids.

Base salts include, but are not limited to, those formed withpharmaceutically acceptable cations, such as sodium, potassium, lithium,calcium, magnesium, ammonium and alkylammonium.

Basic nitrogen-containing groups may be quarternised with such agents aslower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl and diethylsulfate; and others.

The compounds and salts of the invention may be presented in the form ofa prodrug. The term “prodrug” is used in its broadest sense andencompasses those derivatives that are converted in vivo to thecompounds of the invention. A prodrug may include modifications to oneor more of the functional groups of a compound of the invention.

The phrase “a derivative which is capable of being converted in vivo” asused in relation to another functional group includes all thosefunctional groups or derivatives which upon administration into a mammalmay be converted into the stated functional group. Those skilled in theart may readily determine whether a group may be capable of beingconverted in vivo to another functional group using routine enzymatic oranimal studies.

It will also be recognised that compounds of the invention may possessasymmetric centres and are therefore capable of existing in more thanone stereoisomeric form. The invention thus also relates to compounds insubstantially pure isomeric form at one or more asymmetric centres eg.,greater than about 90% ee, such as about 95% or 97% ee or greater than99% ee, as well as mixtures, including racemic mixtures, thereof. Suchisomers may be prepared by asymmetric synthesis, for example usingchiral intermediates, or by chiral resolution.

Compounds of formula (I), (II) and (III) possess a heteroaryl moietylinked to a thienyl or thiazolyl moiety through a single bond. A personskilled in the art would be aware of reactions to link two heteroarylmoieties, for example using the Suzuki reaction. In the Suzuki reactiona heteroaryl halide, such as a bromide, or heteroaryl triflate is mixedwith a heteroaryl borane in the presence of a palladium catalyst andbase to produce a biheteroaryl moiety. Suitable palladium catalystswould be known to a person skilled in the art and includetetrakis-(triphenylphosphine)palladium(0). A range of bases also may beused, such as caesium fluoride and sodium carbonate.

One or both of the heteroaryl rings employed in the Suzuki reaction maybe further functionalised before, or after the reaction. In one example,if an ester-substituted heteroaryl bromide is used in the abovereaction, then following the reaction the ester group may be hydrolysed,and then treated with various other reagents to form, for example, anamide bond, a reduced amide, an alkenyl bond, an ester, or an ether.This step may be used to incorporate functionality at, for example, R²or to the thienyl moiety or thiazolyl moiety (for compounds of formula(I)), or R², R¹² or R¹³ (for compounds of formula (II) or (III)).

Other methods to prepare compounds of formula (I), (II) and (III) wouldbe known to a person skilled in the art. Two general procedures areoutlined below in the Examples.

A person skilled in the art will be aware that during synthesis, of thecompounds of the invention, some substituents may be reactive underconditions used and must be disguised or protected to prevent unwantedside reactions. Suitable protecting groups for protecting reactivegroups from unwanted reactions are provided in Green and Wuts,Protective Groups in Organic Synthesis.

While it is possible that, for use in therapy, a compound of theinvention may be administered as a neat chemical, the active ingredientis especially presented as a pharmaceutical composition.

Thus, in a further aspect of the invention there is provided apharmaceutical composition comprising a compound of formula (II) or(III) and at least one pharmaceutically acceptable carrier.

The carrier(s) must be “acceptable” in the sense of being compatiblewith the other ingredients of the composition and not deleterious to therecipient thereof.

Pharmaceutical compositions include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.The compounds of the invention, together with a conventional adjuvant,carrier, excipient, or diluent, may thus be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, in the form of suppositories forrectal administration; or in the form of sterile injectable solutionsfor parenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. Formulations containingten (10) milligrams of active ingredient or, more broadly, 0.1 to twohundred (200) milligrams, per tablet, are accordingly suitablerepresentative unit dosage forms. The compounds of the present inventioncan be administered in a wide variety of oral and parenteral dosageforms. It will be obvious to those skilled in the art that the followingdosage forms may comprise, as the active component, either a compound ofthe invention or a pharmaceutically acceptable salt or derivative of thecompound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity, in suitable proportions and compacted in theshape and size desired.

The powders and tablets especially contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient, sized moulds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising active agent in a flavoured base, usually sucroseand acacia or tragacanth; pastilles comprising the active ingredient inan inert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multidose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising, spray pump. To improve nasal delivery andretention the compounds according to the invention may be encapsulatedwith cyclodextrins, or formulated with their agents expected to enhancedelivery and retention in the nasal mucosa.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).

Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 1 to 10 microns or less.Such a particle size may be obtained by means known in the art, forexample by micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are especially in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

In one embodiment, the composition is a liquid or powder for intranasaladministration, a tablet or capsule for oral administration or a liquidfor intravenous administration.

The invention will now be described with reference to the followingExamples which illustrate some aspects of the present invention.However, it is to be understood that the particularity of the followingdescription of the invention is not to supersede the generality of thepreceding description of the invention.

EXAMPLES Synthesis

Nuclear Magnetic Resonance spectra were recorded at 400 MHz (¹H)/100 MHz(¹³C) on a Varian Gemini-400. ¹H and ¹³C chemical shifts (δ) are givenin parts per million (ppm) using residual protonated solvent (DMSO-d₆)as an internal standard. Coupling constants are given in Hertz (Hz). Thefollowing abbreviations are used: s=singlet, d=doublet, t=triplet,m=multiplet, bs=broad signal. Low resolution mass spectral data wererecorded on a API2000 (TOF MS ES+) instrument (Applied Biosystems). Highresolution mass spectral data was obtained on a PE Sciex API QSTARPulsar (ES-qTOF) (Perkin Elmer, Waltham, Mass., USA) instrument usingACP (acyl carrier protein) (65-714) (C₄₇H₇₅N₁₂O₁₆ (M+H), 1063.5424) andreserpine (C₃₃H₄₀N₂O₉ (M+H), 609.2812) as internal references.Resolution for the instrument was set between 10,000 and 12,000 for allstandards. Analytical reversed-phase high performance liquidchromoatography (HPLC) was performed on a Gemini C₁₈ column (4.6×250 mm)(Phenomenex, Lane Cove, NSW, Australia). Preparative reversed phase HPLCwas performed on a Gemini 10μ C₁₈ column (22×250 mm) (Phenomenex) orJupiter 10μ 300 Å C₁₈ column (21.2×250 mm) (Phenomenex). Separationswere achieved using linear gradients of buffer B in A (A=0.1% aqueousTFA; B=90% CH₃CN, 10% H₂O, 0.09% TFA) at a flow rate of 1 mL/min(analytical) and 20 mL/min (preparative).

Rink amide resin (sv=0.65 mM/g),2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU) and all N_(α)-Fmoc-amino acids were peptide synthesis gradepurchased from IRIS Biotech (Marktredwitz, Germany). Dichloromethane,diisopropylethylamine, N,N-dimethylformamide, and trifluoroacetic acidwere obtained from Auspep (Parkville, VIC, Australia). HPLC gradeacetonitrile and methanol were purchased from Labscan (Gliwice, Poland).All other reagents and solvents were purchased from Sigma-Aldrich, AlfaAesar (Lancashire, England), Combi-Blocks (San Diego, Calif., USA),Oakwood Products (West, Columbia, S.C., USA), Frontier Scientific(Logan, Utah, USA), Boron Molecular (Noble Park, VIC, Australia) andTrans World Chemicals (Rockville, Md., USA). Abbreviations: TFA,trifluoroacetic acid; DCM, dichloromethane; EtOAc, ethyl acetate; EtOH,ethanol; DMSO, dimethylsulfoxide; DMF, N,N-dimethylformamide; HBTU,O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate;PyBrOP, benzotriazole-1-yloxytripyrrolidinophosphoniumhexafluorophosphate; DIEA, N,N-diisopropylethylamine; Pd(PPh₃)₄,Tetrakis-(triphenylphosphine)palladium(0); CsF, caesium fluoride; CuI,copper(I)iodide; MgSO₄, magnesium sulphate.

General, Procedure a (On-Resin Synthesis)

Functionalized Rink amide polystyrene resin (0.325 mM, 0.5 g) wasderivatized with Fmoc-AA using in situ neutralization/HBTU activationprotocols for Fmoc chemistry. After removal of the Fmoc group to providea primary amine, a carboxy-substituted heteroaryl bromide was coupled tothe primary amine.

The bromoheteroaryl-functionalized resin (0.325 mM) was placed in areaction vessel under nitrogen atmosphere. Dimethylether (DME) (5 mL)was degassed and added to the resin, followed by addition of neatPd(PPh₃)₄ (81 mg, 0.07 mM). A solution of a thiopheneboronic acid orthiazoleboronic acid (1.3 mM) in degassed EtOH (1 mL) was added to theresin, and the mixture was agitated for 5 min; CsF (162 mg, 1.3 mM) wasadded neat. The mixture was agitated 16 h at 60° C. before excessreagents were removed by filtration, and the resin was washed with DMF(3×) and DCM (3×) to yield resin bound compound.

The resin was dried for several hours under reduced pressure and placedin a cleavage vessel. The resin was treated with a mixture of TFA/H₂O92:8 for an hour. TFA was blown off under nitrogen atmosphere and thedry cleaved crude product was re-dissolved in a solution of 30% A and70% B (as defined above) and separated from the resin. Preparative HPLC,followed by freeze-drying, gave the pure product as a white solidmaterial.

General Procedure B (Solution Based Synthesis)

An ester-substituted heteroaryl bromide (1.5 mM) was dissolved intoluene (7 mL) and in a separate vessel a thiopheneboronic acid orthiazoleboronic acid (2.0 mM) was dissolved in toluene (7 mL) andethanol (1.5 mL). 2.0 mL of sodium carbonate (2.5 M) was added to thedissolved ester-substituted heteroaryl bromide. The catalyst Pd(PPh₃)₄(35 mg, 0.03 mM) was added to the dissolved ester-substituted heteroarylbromide followed by the dissolved thiophene- or thiazole-boronic acid,and the flask was evacuated and refilled with argon five times. Themixture was stirred at 80° C. for 2 hours. The mixture was filteredthrough celite with EtOAc (100 mL). The organic layer was separated,dried over MgSO₄ and the solvent was removed under reduced pressure.Preparative HPLC, followed by freeze-drying, gave the pure product as awhite solid material.

The pure fractions were collected and the ester group was hydrolysedwith 1 M lithium hydroxide (LiOH) in tetrahydrofuran (THF) for 16 h. Thesolvent was removed under reduced pressure receiving the compound with afree acid.

The functionalized carboxylic acid (1 eq) and amine (2 eq) were placedin a reaction vessel under nitrogen atmosphere. PyBrOP (2 eq) was addedneat together with DIEA (2.2 eq) and DMF. The mixture was stirred for 24h at room temperature. Solvent was removed by evaporation using aGeneVac Atlas HT-8 speed evaporation system. Preparative HPLC, followedby freeze-drying of the appropriate fractions, gave the pure product asa white solid material.

Example Compounds

N-(1-amino-1-oxo-3-phenylpropan-2-yl)-6-(thiophen-2-yl)-nicotinamide (3)was prepared via procedure A, using Fmoc-protected-L-phenylalanine (1.3mM), 6-bromopyridine-3-carboxylic acid (0.975 mM) and 2-thiopheneboronicacid (1.3 mM). Yield (7.5 mg, 6.57%); ¹H NMR (400 MHz, DMSO-d₆): δ 2.94(dd, J=10.8 Hz, J=30 Hz, 1H), 3.12 (dd, J=9.2 Hz, J=30 Hz, 1H), 4.64(ddd, J=8.4 Hz, J=9.2 Hz, J=10.8 Hz, 1H), 7.12 (bs, 1H), 7.13-7.34 (m,6H), 7.58 (bs, 1H), 7.69 (dd, J=1.2 Hz, J=4.8 Hz, 1H), 7.87 (dd, J=1.2Hz, J=3.6 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 8.13 (dd, J=2 Hz, J=8.4 Hz,1H), 8.71 (d, J=8.4 Hz, 1H), 8.83 (d, J=0.8 1H). ¹³C NMR (100 MHz,DMSO-d₆): δ 173.6, 164.9, 154.2, 149.1, 144.0, 138.9, 136.6, 130.2,129.6 (2C), 129.1, 128.5 (2C), 128.1, 127.1, 126.7, 118.4, 55.1, 37.7.ESI-HRMS calculated for C₁₉H₁₇N₃O₂S [M+H]⁺352.1119. Found: 352.1109.

N-benzhydryl-6-(thiophen-2-yl)nicotinamide (4) was prepared viaprocedure B, using methyl 6-bromopicolinate (1.5 mM), 2-thiopheneboronicacid (2 mM) and benzhydrylamine (2 eq). Yield (0.45 mg/0.7%); ESIcalculated for C₂₃H₁₈N₂OS [M+H]⁺: 370.1. Found: 371.0.

N-benzyl-6-(thiophen-2-yl)nicotinamide (5) was prepared via procedure B,using methyl 6-bromopicolinate (1.5 mM), 2-thiopheneboronic acid (2 mM)and phenylmethanamine (2 eq). Yield (5.38 mg/9.1%); ¹H NMR (400 MHz,DMSO-d₆): δ 4.50 (d, J=6 Hz, 2H), 7.19 (t, J=9.6 Hz, 1H), 7.22 (q,J=17.6 Hz, 1H), 7.27-7.33 (m, 4H), 7.70 (d, J=4.8 Hz, 1H), 7.89 (d,J=3.6 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 8.25 (dd, J=1.6 Hz, J=8.4 Hz,1H), 8.97 (d, J=2.4 Hz, 1H), 9.19 (t, J=11.6 Hz 1H). ESI calculated forC₁₇H₁₄N₂OS [M+H]⁺: 294.1. Found: 295.1.

(3,4-dihydroisoquolin-2(1H)-yl)(6-(thiophen-2-yl)pyridin-3-yl)methanone(6) was prepared via procedure B, using methyl 6-bromopicolinate (1.5mM), 2-thiopheneboronic acid (2 mM) and 1,2,3,4-tetrahydroisoquinoline(2 eq). Yield (12.67 mg/22%); ¹H NMR (400 MHz, DMSO-d₆): δ 2.81 (d,J=11.6 Hz, 2H), 3.61 (s, 1H), 3.84 (s, 1H), 4.64 (s, 1H), 4.76 (s, 1H),7.06-7.25 (m, 6H), 7.69 (d, J=4.8 Hz, 1H), 7.88 (d, J=4 Hz, 1H), 7.91(d, J=8.4 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 8.61 (d, J=0.8 Hz, 1H). ¹³CNMR (100 MHz, DMSO-d₆): δ 169.3, 153.1, 148.1, 144.2, 136.5, 134.8,133.3, 130.5, 129.8, 129.1 (2C), 127.0, 126.8, 126.7, 118.7, 113.7,49.5, 44.8, 29.3. ESI calculated for C₁₉H₁₆N₂OS [M+H]⁺: 320.1. Found:321.0.

(2,3-dihydrospiro[indene-1,4′-piperidin]-1′-yl)(6-(thiophen-2-yl)pyridin-3-yl)methanone(7) was prepared via procedure B, using methyl 6-bromopicolinate (1.5mM), 2-thiopheneboronic acid (2 mM) and2,3-dihydrospiro[indene-1,4′-piperidine] (2 eq). Yield (0.85 mg/2.1%).ESI calculated for C₂₃H₂₂N₂OS [M+H]⁺: 374.2. Found: 375.0.

1-(4-phenyl-1-(6-(thiophen-2-yl)nicotinoyl)piperidin-4-yl)ethanone (8)was prepared via procedure B, using methyl 6-bromopicolinate (1.5 mM),2-thiopheneboronic acid (2 mM) and 1-(4-phenylpiperidin-4-yl)ethanone (2eq). Yield (2.48 mg/5.1%). ESI calculated for C₂₃H₂₂N₂O₂S [M+H]⁺: 390.5.Found: 390.9.

4-((6-(thiophen-2-yl)nicotinamido)methyl)benzoic acid (9) was preparedvia procedure B, using methyl 6-bromopicolinate (1.5 mM),2-thiopheneboronic acid (2 mM) and 4-(aminomethyl)-benzoic acid (2 eq).Yield (2.78 mg/5.2%); ¹H NMR (400 MHz, DMSO-d₆): δ 4.56 (d, J=6 Hz, 2H),7.19 (t, J=8.8 Hz, 1H), 7.43 (d, J=8 Hz, 2H), 7.70 (d, J=5.2 Hz, 1H),7.89-7.91 (m, 3H), 8.02 (d, J=8.4 Hz, 1H), 8.25 (dd, J=2.4 Hz, J=8.4 Hz,1H), 8.98 (d, J=2.4 Hz, 1H), 9.26 (d, J=6 Hz, 1H). ¹³C NMR (100 MHz,DMSO-d₆): δ 167.6, 165.1, 154.4, 149.0, 144.9, 144.0, 136.5, 130.2,129.9 (2C), 129.8, 129.2, 128.1, 127.7 (2C), 127.2, 118.6, 42.9. ESIcalculated for C₁₈H₁₄N₂O₃S [M+H]⁺: 338.1. Found: 339.0.

(1-(methylsulfonyl)spiro[indoline-3,4′-piperidin]-1′-yl)(6-(thiophen-2-yl)pyridin-3-yl)methanone(10) was prepared via procedure B, using methyl 6-bromopicolinate (1.5mM), 2-thiopheneboronic acid (2 mM) and1-(methylsulfonyl)spiro[indoline-3,4′-piperidine] (2 eq). Yield (16.26mg/26.4%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.65 (s, 1H), 1.77 (s, 1H), 1.87(d, J=10.8 Hz, 2H), 2.48 (d, J=1.6 Hz, 2H), 3.01-3.04 (m, 3H), 3.61 (s,1H), 3.91-3.94 (m, 2H), 4.49 (s, 1H), 7.06 (t, J=13.2 Hz, 1H), 7.17-7.27(m, 3H), 7.41 (d, J=7.6 Hz, 1H), 7.68 (dd, J=1.2 Hz, J=5.2 Hz, 2H), 7.87(dd, J=1.2 Hz, J=3.8 Hz, 1H), 7.91 (dd, J=2.4 Hz, J=8.4 Hz, 1H), 7.98(d, J=8.4 Hz, 1H), 8.61 (d, J=2.4 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆): δ167.2, 152.9, 148.0, 144.1, 141.4, 138.9, 136.5, 130.4, 129.7, 129.1,128.9, 126.7, 124.3, 124.0, 118.7, 113.2, 58.7, 44.9, 43.2, 36.3, 35.8,34.7 (2C). ESI calculated for C₂₃H₂₃N₃O₃S₂ [M+H]⁺: 453.1. Found: 453.8.

1-(1-(6-(thiophen-2-yl)nicotinoyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one(11) was prepared via procedure B, using methyl 6-bromopicolinate (1.5mM), 2-thiopheneboronic acid (2 mM) and1-(piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (2 eq). Yield (14.04mg/47.6%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.74 (s, 1H), 2.35 (m, 1H), 2.48(s, 1H), 2.98 (s, 1H), 3.25 (s, 1H), 3.74 (s, 1H), 4.42 (m, 1H), 4.62(s, 1H), 6.96 (d, J=6.8 Hz, 2H), 7.18 (t, J=12 Hz, 1H), 7.36 (d, J=7.6Hz, 1H), 7.68 (d, J=4 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.93 (d, J=1.6Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 8.62 (d, J=0.8 Hz, 1H). ¹³C NMR (100MHz, DMSO-d₆): δ 167.3, 154.2, 153.0, 148.0, 144.1, 136.5, 130.4, 129.7,129.5, 129.1, 128.7, 126.7, 121.2, 121.0, 118.7, 109.4, 50.2, 47.3,41.7, 29.5, 28.9. ESI calculated for C₂₂H₂₀N₄O₂S [M+H]⁺: 404.1. Found:404.9.

(S)—N-(1-(naphthalen-2-yl)ethyl)-6-(thiophen-2-yl)nicotinamide (12) wasprepared via procedure B, using methyl 6-bromopicolinate (1.5 mM),2-thiopheneboronic acid (2 mM) and (S)-1-(naphthalen-2-yl)ethanamine (2eq). Yield (12.3 mg/14.5%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.58 (d, J=7.2Hz, 3H), 5.30-5.37 (m, 1H), 7.19 (t, J=5.2 Hz, 1H), 7.44-7.51 (m, 5H),7.58 (dd, J=1.6 Hz, J=8.4 Hz, 1H), 7.70 (dd, J=0.8 Hz, J=5 Hz, 1H),7.85-7.88 (m, 3H), 7.90 (d, J=3.2 Hz, 2H), 8.00 (d, J=8.4 Hz, 1H), 8.26(dd, J=2 Hz, J=8.2 Hz, 1H), 8.98 (d, J=2.4 Hz, 1H), 9.06 (d, J=8 Hz,1H). ¹³C NMR (100 MHz, DMSO-d₆): δ 164.3, 154.3, 149.2, 142.5, 136.6,133.3, 132.1, 130.1, 129.1, 128.4 (2C), 128.1 (2C), 127.9, 127.1, 126.6,126.1, 125.4, 124.6, 118.4, 49.2, 22.5. ESI calculated for C₂₂H₁₈N₂OS[M+H]⁺: 358.1. Found: 358.9.

1-(1-(6-(thiophen-2-yl)nicotinoyl)piperidin-4-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one(13) was prepared via procedure B, using methyl 6-bromopicolinate (1.5mM), 2-thiopheneboronic acid (2 mM) and1-(piperidin-4-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one (2 eq). Yield (26.3mg/43.2%); ¹H NMR (400 MHz, DMSO-d₆): δ 1.83 (d, J=26.8 Hz, 2H), 2.46(d, J=16 Hz, 2H), 2.96 (s, 1H), 3.33 (s, 1H), 3.72 (s, 1H), 4.20-4.22(m, 1H), 4.61 (s, 1H), 5.12 (s, 2H), 7.10 (t, J=14.4 Hz, 1H), 7.17-7.18(m, 1H), 7.27 (d, J=7.2 Hz, 1H), 7.32-7.39 (m, 2H), 7.67 (dd, J=1.2 Hz,J=5 Hz, 1H), 7.86 (dd, J=1.2 Hz, J=2.4 Hz, 1H), 7.87 (dd, J=1.2 Hz, J=2Hz, 7.98 (d, J=8.4 Hz, 1H), 8.56 (d, J=2 Hz, 1H). ¹³C NMR (100 MHz,DMSO-d₆): δ 167.1, 153.0, 152.4, 148.0, 144.1, 138.9, 136.4, 130.4,129.8, 129.5, 129.1, 126.7, 125.3, 123.5, 123.1, 118.7, 114.6, 66.8,55.7, 47.2, 41.9, 29.1, 28.2. ESI calculated for C₂₂H₂₁N₃O₃S [M+H]⁺:419.1. Found: 419.9.

Further example compounds are shown in Table 1 below.

Biological Assays

Materials

Glutathione, 1-chloro-2,4-dinitrobenzene, indomethacin, nocodazole, werepurchased from Sigma-Aldrich Pty Ltd (Castle Hill, NSW, Australia).Compounds 1 and 2 are known inhibitors of H-PGDS (Aritake, 2006; Hohwy,2008). Compound 1 (HQL-79) was obtained from Cayman Chemical (Ann Arbor,Mich., USA). Compound 2 was purchased at Ryan Scientific (Mt. Pleasant,S.C., USA).

Protein Expression and Purification

H-PGDS was expressed and purified as described previously (Jowsey,2001). Briefly, H-PGDS was expressed in Escherichia coli strain BL21 DE3transformed with the pET17b HPGDS expression construct, grown overnightat 37° C. in 250 ml of Luria-Bertani medium supplemented with 100 μg/mlampicillin. After 24 h, without induction, bacteria were harvested bycentrifugation at 5000 g for 20 min at 4° C.; cell pellets were kept at−70° C. until required. Cells were resuspended in 25 ml of ice-coldphosphate buffered saline (PBS), pH 7.4, containing 1 mM DTT, 0.5%Triton X-100 and EDTA-free protease inhibitor tablets (F. Hoffmann-LaRoche, Dee Why, NSW, Australia); and incubated with rotation for 30 minsat 4° C. Cells were then lysed by sonication at 90-100 W over 3×1 minintervals, while incubated on ice; the lysate clarified bycentrifugation at 18000 g for 10 min at 4° C.

The supernatant was then applied to a GSTPrep FF 16/10 columnpre-equilibrated with PBS, pH 7.4, and 1 mM DTT, at 0.4 ml/minute usingan AKTA explorer 100 (GE Healthcare, Rydalmere, NSW, Australia), thenwashed with 5 column volumes of the same buffer at 1 ml/min. BoundH-PGDS was eluted in 5 column volumes of 15 mM reduced glutathione in 50mM Tris, pH 9.0, at 0.5 ml/min, and dialysed against 100 volumes of 5 mMTrisCl, pH 8.0. The protein was concentrated to 20 mg/ml, as determinedby the method of Bradford (Bradford, 1976) using an Amicon Ultra-4centrifugal filter device (Millipore, North Ryde, NSW, Australia)following manufacturers recommendations. Glycerol was added to a finalconcentration of 10% (v/v) prior to storage at −20° C.

Enzyme Assays

The H-PGDS catalyzed conjugation of GSH and 1-chloro-2,4-dinitrobenzene(CDNB) was used as the biochemical assay for enzyme inhibition.Reactions were performed in 96 well plate format, and product formationwas followed at A340 nm over a 10 min interval at 25° C. using aPOWERWAVE XS microplate scanning spectrophotometer (Bio-Tek Instruments,Winooski, Vt., USA). Reactions were performed in 0.1 M Tris HCl, pH 8.0containing 2 mM MgCl₂, 1 mM CDNB, 2 mM GSH, 2.5 ng/μ1 purified H-PGDSand 10% (v/v) ethanol in a 200 μl reaction volume. IC₅₀ values werecalculated from rates of conjugation activity determined at eightconcentration points bracketing the IC₅₀, where compound solubilityallowed, and were corrected for background activity at the same solventconcentrations. All compounds were made up in 100% DMSO and diluted with0.1 M Tris HCl, pH 8.0 with 2 mM MgCl₂. I₅₀ and IC₅₀ values weredetermined at a final DMSO composition of no greater than 4% v/v for allcompounds. Non-linear regression analysis and IC₅₀ calculations wereperformed using GraphPad Prism version 4.0c. The results are shown inTable 1.

TABLE 1

Compound R² R¹ Mass/yield I_([50]) IC₅₀ (μM)  3

 7.5 mg/6.6% 97.0 ± 2.4  1.2 ± 1.0  4

 0.45 mg/0.7% 28.5 —  5

 5.38 mg/9.1% 99.5 ± 0.8 0.597 ± 1.2  6

12.67 mg/22% 72.3 ± 1.5 n/a-  7

 0.85 mg/2.1% 91.0 ± 0.1  1.97 ± 1.2  8

 2.48 mg/5.1% 58.7 ± 0.8 n/a-  9

 2.78 mg/5.2% 98.3 ± 1.1  0.66 ± 1.1 10

16.26 mg/26.4% 90.4 ± 0.5  1.23 ± 1.1 11

14.04 mg/47.6% 90.4 ± 0.7  1.22 ± 1.4 12

 12.3 mg/14.5% 99.8 ± 0.3 0.086 ± 1.1 13

 26.3 mg/43.2% 87.9 ± 1.1  3.40 ± 1.4 14

14.16 mg/16.6% 83.4 ± 1.5  1.7 ± 1.8 15

 0.64 mg/0.7% 19.4 ± 1.4 — 16

 0.91 mg/1.8% 89.4 ± 4.7  1.4 ± 1.3 17

 1.7 mg/3.4% 95.0 ± 1.1  2.0 ± 1.1 18

 1.34 mg/2.9% 65.5 ± 7.7  5.1 ± 1.1 19

 0.42 mg/1% 94.8 ± 2.4  3.2 ± 1.6 20

 0.46 mg/1% 67.9 ± 1.6 n/a 21

 0.54 mg/1.1% 97.4 ± 0.8  0.38 ± 1.1 22

 0.46 mg/0.9% 34.6 ± 2.1 n/a 23

 1.08 mg/2.2% 91.6 ± 0.8  1.87 ± 1.1 24

94.6 ± 0.3  0.86 ± 1.2 25

96.9 ± 1.0  0.18 ± 1.2 IC₅₀ values were calculated from triplicateexperiments, and are presented as IC₅₀ ± Standard Error of the Mean.I_([50]) is percent inhibition at 50 μM, and is presented as the Mean ±Standard Error of triplicate experiments. ‘—’ indicates that IC₅₀ valuescould not be retrieved under the assay conditions.Effects of Selected H-PGDS Inhibitors on the Production of OtherProstaglandins, Prostacyclins and Thromboxanes

A selection of compounds were assessed for their ability to inhibitinducible PGD₂ production in two inflammation-relevant cell models,mouse primary bone marrow-derived macrophages (BMM) responding tolipopolysaccharide (LPS), and the human megakaryocyte cell line, MEG-01Sresponding to PMA (Phorbol 12-myristate 13-acetate) differentiation,followed by triggering with the calcium ionophore A23187.

Cell Culture

All bone marrow-derived macrophages (BMM) were obtained by culturingbone marrow cells from the femurs of 6 to 8 week old C57BL/6 male micein RPMI 1640 medium (Invitrogen Life Technologies, Carlsbad, Calif.,USA) supplemented with 10% Fetal calf serum (Invitrogen) 20 U/mlpenicillin and 20 μg/ml streptomycin (Invitrogen), 2 mM L-glutamine(Glutamax-1, Invitrogen) in the presence of 10⁴ U/ml (100 ng/mL)recombinant human CSF-1 (a gift from Chiron, Emeryville, Calif.) onbacteriological plastic plates for 7 days. The human megakaryocytic cellline MEG-01S was obtained from the American Type Culture Collection.MEG-01S were maintained in the same media as for BMM, supplemented with1 mM Sodium Pyruvate (Invitrogen).

Determination of mRNA Expression by Quantitative PCR (qPCR)

As PGD₂ is produced by both H-PGDS and the genetically distinct L-PGDS,quantitative RT-PCR was first used to assess relative mRNA levels as anindicator of enzyme expression in these cell lines.

RNA was extracted from 3×10⁶ cells and cDNA synthesised as describedpreviously (Irvine, J Leuk Biol, 2009). Briefly, RNA was extracted usingRNeasy kits (Qiagen, Valencia, Calif., USA), contaminating genomic DNAremoved using RNeasy on-column DNase (Qiagen) and cDNA was synthesisedusing Superscript III (Invitrogen) and oligo(dT) primer. Transcriptabundance was quantitated using gene-specific primer pairs and the SYBRgreen system (Applied Biosystems, Foster City, Calif., USA) relative tohypoxanthine guanine phosphoribosyl transferase (HPRT) levels using thepower delta Ct method. Primer efficiencies for the respective human andmouse H-PGDS and L-PGDS primer pairs were measured over a cDNA dilutionseries, and were used to normalize expression, such that comparisonscould be made of mRNA levels for H-PGDS versus L-PGDS (for human andmouse). Primer pairs used were Human H-PGDS gene, Human L-PGDS gene,Human HPRT gene, Mouse H-pgds gene, Mouse L-pgds gene and Mouse Hprtgene, as shown in Table 2.

TABLE 2  Gene Forward Reverse Human TCACCAGAGCCTAGCAATAGCTGCCCAAGGAAAACATGAC H-PGDS CA A Human CCTGACCTCCACCTTCCTCATCGGTCTCCACCACTGACAC L-PGDS Human TCAGGCAGTATAATCCAAAGAGTCTGGCTTATATCCAACA HPRT ATGGT CTTCC Mouse AAGCACCTCGCCTTCTGAAACAGTAGAAGTCTGCCCAGGT H-pgds TACAT Mouse CAGAGGGCTGGTCACATGGTAGGCAAAGCTGGAGGGTGTA L-pgds G Mouse GCAGTACAGCCCCAAAATGGAACAAAGTCTGGCCTGTATC Hprt CAA

Results show that H-PGDS is the predominant PGDS expressed by mouse BMMand human MEG-01S cells. Quantitative RT-PCR data from BMM and MEG-01Scells shows that H-PGDS mRNA was expressed at much higher levels (1000×)than L-PGDS in both mouse BMM and human MEG-01S cells.

BMM were treated with LPS over a time course and relative geneexpression for H-PGDS and L-PGDS was quantitated. LPS was shown toinduce L-PGDS expression in macrophages and H-PGDS was also regulated byLPS: Nonetheless, the increase in L-PGDS mRNA expression in response toLPS was very modest in comparison to the high basal expression of H-PGDSin BMM. It was concluded that H-PGDS is the major PGDS expressed by bothhuman MEG-01S cells and mouse BMM, implying that this enzyme is likelyto be the dominant source of PGD₂ production in these cell types.

Prostaglandin Release from Cells and Cell Viability:

Procedure: Prostaglandin Release from Cells

BMM were seeded overnight at 2×10⁵ cells/ml in 24 well plates beforetreatment with compound at either 10 μM or 0.1-100 μM for 24 h in thepresence or absence of lipopolysaccharide (LPS) from SalmonellaMinnesota (Sigma-Aldrich) at a final concentration of 10 ng/ml. MEG-01Swere seeded at 2×10⁵ cells/ml and stimulated with PMA (Phorbol12-myristate 13-acetate) (Sigma-Aldrich) at a final concentration of 0.1μM for 16 h. Compound (0.3-100 μM) was added 30 min prior to stimulationwith 5 μM Calcium Ionophore A23187 (Sigma-Aldrich) for 30 min. Allcompounds were dissolved in DMSO and diluted in cell culture medium suchthat the final concentration of DMSO did not exceed 0.1%. Supernatantswere collected and samples were analysed for PGD₂ using Prostaglandin D2Mox Express EIA kits, PGE₂ using Prostaglandin E2 Express EIA kits, theprostacyclin derivative 6-keto PGF_(1α) using the 6-keto ProstaglandinF_(1α) EIA Kit and the Thromboxane A₂ derivative TXB₂ using theThromboxane B₂ Express EIA kit (Cayman Chemical) according to themanufacturer's instructions.

Procedure: Cell Viability Assays

Known inhibitors 1 and 2, along with compound 3, were used to treat BMMat three doses (10, 30, 100 μM) in the presence of LPS for 24 h and cellviability was measured by MTT assay. BMM were seeded at 1×10⁵ cells/wellin 96 well plates and treated for 24 h with LPS (10 ng/ml) and compoundsat 10, 30 and 100 μM. MEG-01S were PMA differentiated overnight beforecompounds were added for a further 24 h at 10, 30 and 100 μM. Cellviability was measured by MTT (Sigma-Aldrich) assay as describedpreviously (Irvine, FASEB J, 2006).

Prostaglandin D₂ Production in LPS-Activated BMMs

FIG. 1A shows the results of tests on compound 3 to assess its abilityto inhibit PGD₂ production in LPS-activated BMMs. The compound wastested with 10 μM of compound and LPS (10 ng/ml) for 24 h. The averagePGD₂ production from three independent experiments plus SEM is shown. *indicates p<0.05 versus LPS treatment alone. (Student's t test).

BMM Cell Viability

Compound 3 did not affect BMM viability at 10 μM or 100 μM, as assessedby MIT assay (FIG. 1B). Compounds 1 and 2, identified by others asH-PGDS inhibitors (Hohwy, 2008), had modest but significant effects onBMM cell viability (FIG. 1B). In FIG. 1B data show the average of fourindependent experiments plus SEM. * indicates p<0.05 versus control (onesample t test where the hypothetical mean is 100).

Prostaglandin Production in LPS-Activated BMMs: Compound 3

Compound 3 was further characterised along with the H-PGDS inhibitors 1(HQL-79) (Aritake, 2006) and 2 (Hohwy, 2008) in LPS-activated BMM.

BMM were treated with increasing concentrations (0-100 μM) of compounds1, 2 and 3 with appropriate vehicle controls (Ethanol for 1, DMSO for 3and 2) and with LPS for 24 h. PGD₂ (FIG. 2A), PGE₂ (FIG. 2B)prostacyclin derivative 6-keto PGF_(1α) (FIG. 2C) and Thromboxane A₂derivative TXB₂ (FIG. 2D) levels in supernatants collected from cellswere quantified by EIA. Data show the average of three independentexperiments plus SEM.* indicates p<0.05; ** indicates p<0.01; ***indicates p<0.001 (Student's t test) versus vehicle+LPS.

Compound 3 inhibited PGD₂ production in the sub-micromolar rangedose-dependently (FIG. 2A). The EC₅₀ estimated for compound 3 (˜0.29 μM)was comparable to that estimated for compound 2 (EC₅₀˜0.16 μM), and was˜30 fold better than that estimated for 1. The specificities of 3, 2 and1 were then assessed by comparing effects on LPS-inducible PGE₂, thehydrated prostacyclin derivative 6-keto PGF_(1α) and the thromboxane A₂derivative TXB2 production from BMM (FIG. 2B). Compound 1 showed nodifferential effect in inhibition of PGD₂ versus PGE₂, 6-keto PGF_(1α)or TXB₂, while compound 2 showed only a modest difference. In contrast,compound 3 demonstrated a striking selectivity, significantly inhibitingPGD₂ levels at 1 μM, whilst PGE₂, 6-keto PGF_(1α) and TXB₂ inhibitionwas only observed above 10 μM. Taken together, these data demonstratethat compound 3 displays selectivity and affinity not otherwise observedfor other H-PGDS inhibitors.

PGD₂ Inhibition in Human Megakaryocytes

PGD₂ inhibition in human megakaryocytes by compound 3, and knowninhibitors 1 and 2, were then characterised. PMA (Phorbol 12-myristate13-acetate) differentiated MEG-01S were treated with compounds 1, 2 and3 across a concentration range (0-100 μM) for 30 min prior to 30 minutetreatment with 5 μM Calcium Ionophore A23187. PGD₂ levels in cellculture supernatants were quantitated by EIA (FIG. 3A). Data representthe average of three independent experiments plus SEM. * indicatesp<0.05; **indicates p<0.01; *** indicates p<0.001 (Student's t test)versus vehicle+Ionophore.

Compounds 2 and 3 inhibited A23187-inducible PGD₂ production fromPMA-differentiated MEG-01S human megakaryocytes dose-dependently, while1 displayed very modest activity at 100 μM (FIG. 3A).

MEG-01S Cell Viability

The effect of the compounds on MEG-01S cell viability was measured byMTT assay after 24 h treatment across the concentration range 0-100 μMof compounds (FIG. 3B). Data represent the average of 4 independentexperiments plus SEM.

Again, compound 3 had little effect on MEG-01S cell viability (FIG. 3B),as did compounds 1 and 2, suggesting that inhibition of PGD₂ productionoccurred through enzyme inhibition.

COX1 and COX2 Enzyme Assays

As inhibition of COX1 and/or 2 may also have a negative impact on PGD₂production in cells, compound 3, along with known compound 2, was testedagainst purified COX1 and 2 isoforms at 1, 10 and 100 μM (FIG. 4). Testswere also performed on the well-characterized COX inhibitor,indomethacin, as a positive control. Data represent the average of threeindependent experiments plus SEM. * indicates p<0.05; (One sample t testwhere the hypothetical mean is 100).

COX1 and COX2 enzyme assays were performed using the Colorimetric COX(Ovine) Inhibitor Screening Assay kit (Cayman Chemical) according to themanufacturers instructions.

No inhibition of either COX isoform was observed for the H-PGDSinhibitors, whilst indomethacin significantly inhibited the activity ofboth COX1 and COX2 (FIG. 4). This data further supports the selectivityfor PGD₂ synthesis inhibition of this series of compounds.

Pharmacokinetics and Rat Target Modulation assay

Male adult Sprague Dawley rates (˜165 g) received a single oral bolusdose of 40 mg/kg of compound 3 in a 0.5% methylcellulose/0.1% Tween80 byoral gavage. Rats were sacrificed when collecting blood and spleensamples just prior to dosing and at 0.5 hours, 2 h, 8 h and 24 h (n=3rats per time point), and the plasma concentration of compound 3 and thespleen PGD₂ concentration was measured at each time point.

Procedure: Blood Samples

Blood samples were removed and kept cold at approximately 4° C.immediately after collection to minimize degradation and centrifuged assoon as possible at approximately 4000×g for 10 min. The plasma wastransferred to a clean, pre-labelled polypropylene tube and frozen.Samples were stored at −20° C. as soon as possible after collection tominimise degradation of the test item.

Plasma concentrations of 3 were determined using a screening LC-ms/msmethod developed using the following parameters:

Mobile Phase A: 5% Acetonitrile/water, 0.1% TFA; B: 95%Acetonitrile/water, 0.09% TFA. Flow rate: 400 μl/min Gradient: 60% B for0.5 min, up to 100% B in 1 min and remain at 100% B for a further 0.7min. Column Phenomenex, Gemini C18, 150 × 2.0 mm, 5μ Mass Spectrometer4000 Q TRAP Polarity positive Transition m/z 353/307 and 352/161

Samples were analysed alongside plasma standards. Concentration datawere determined by back calculation from standard curve.

Procedure: Spleen Samples

Spleens were excised, weighed and snap frozen in a dry ice/ethanol bath.Tissues were stored at −80° C. until analysis. Spleens were homogenisedin a solution containing 10 mM indomethacin in phosphate buffered saline(PBS) at 1:10 w/v. Samples were centrifuged at 2500 rpm for 5 min at 4°C. The resultant supernatant was diluted and the measurement of PGD₂ wasdetermined by solid-phase extraction (SPE) using cationic solid-phaseextraction cartridges. The SPE eluent was assayed using a screeningLC-MS/MS method against aqueous PGD₂ standards, using the followingLC-MS/MS parameters:

Mobile Phase A: 10 mM Ammonium acetate, pH 8.5; B: 95%Acetonitrile/water. Flow rate: 200 μl/min Gradient: Linear from 20% B to50% B in 10 min Column Phenomenex, Luna Phenyl-hexyl, 3μ, 150 × 2.0 mmMass Spectrometer 4000 Q TRAP Polarity negative Transition m/z 351/271Results

The observed levels of compound 3 in rat serum after oral dosing isillustrated in Table 3. Compound 3 was orally bioavailable and presentin the serum 8 hours post delivery. Compound 3 also showed reduction inPGD₂ activity, 20% at the 8 hour time point.

TABLE 3 Concentration Mean (± sem) Time (h) (ng/mL) N Concentration(ng/mL) 0 BLOQ¹ 3 0 0 BLOQ¹ 0 BLOQ¹ 0.5 177 3  219 ± 24.8 0.5 263 0.5218 2 94.8 3 91.8 ± 9.79 2 73.5 2 107 8 17.3 3 44.3 ± 14.0 8 63.9 8 51.824 BLOQ² 3 0.677 ± 0.177 24 1.03 24 BLOQ² Entries marked BLOQ were Belowthe Lower Limit of Quantitation. BLOQ¹ - treated as 0 in calculating themean. BLOQ² - treated as 0.5 ng/mL (1/2 lower limit of quantitation) incalculating the mean.

REFERENCES

-   K. Aritake et al., Structural and Functional Characterization of    HQL-79, an Orally Selective Inhibitor of Human Hematopoietic    Prostglandin D Synthase, J. Biol. Chem. 2006, 281:15277-15286.-   M. M. Bradford et al., A rapid and sensitive method for the    quantitation of microgram quantities of protein utilizing the    principle of protein-dye binding, Anal. Biochem, 1976, 72:248-254.-   T. W. Green and P. G. M. Wuts, Protective Groups in Organic    Synthesis, John Wiley & Sons, 3^(rd) Edition 1999.-   M. Hohwy et al., Novel Prostaglandin D Synthase Inhibitors Generated    by Fragment-Based Drug Design, J. Med. Chem., 2008, 51:2178-2186.-   I. R. Jowsey et al., Mammalian class Sigma glutathione    S-transferases: catalytic properties and tissue-specific expression    of human and rat GSH-dependent prostaglandin D2 synthases, Biochem.    J., 2001, 359:507-516.-   K. M. Irvine et al., A CSF-1 receptor kinase inhibitor targets    effector functions and inhibits pro-inflammatory cytokine production    from murine macrophage populations, FASEB J, 2006, 20:1921-1923.-   K. M. Irvine et al., Colony-stimulating factor-1 (CSF-1) delivers a    proatherogenic signal to human macrophages, J. Leukoc. Biol., 2009,    85:278-288.

The invention claimed is:
 1. A compound of formula (III) or apharmaceutically acceptable salt thereof:

wherein L and M are both CR¹³; R² is —C(═O)—NR³R⁴; R³ is —CHR⁸R¹¹; R⁴ isselected from hydrogen, hydroxyl, alkyl, haloalkyl, alkenyl, andalkynyl; R⁸ is selected from —CO₂H, —CONH₂, cycloalkyl, cycloalkenyl,aryl, heterocyclyl, heteroaryl, —C₁₋₆alkylR¹⁰, —C₂₋₆alkenylR¹⁰ and—C₂₋₆alkynylR¹⁰; R¹⁰ is selected from cycloalkyl, cycloalkenyl, aryl,heterocyclyl and heteroaryl; R¹¹ is selected from —C₂₋₆alkyl,—C₁₋₆haloalkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylOH,—C₀₋₆alkylCO₂H, —C₀₋₆alkylCONH₂, —C₀₋₆alkylNH₂, —C₀₋₆alkylSH,—C₀₋₆alkylSC₁₋₆alkyl, —C₀₋₆alkylNHC(═NH)NH₂, —C₀₋₆alkylcycloalkyl,—C₀₋₆alkylaryl, —C₀₋₆alkylheterocyclyl and —C₀₋₆alkylheteroaryl; R¹² andR¹³ are independently selected from hydrogen, cyano, nitro, halo,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₀₋₆alkylaryl,—C₀₋₆alkylheteroaryl, —C₀₋₆alkylcycloalkyl, —C₀₋₆alkylcycloalkenyl,—C₀₋₆alkylheterocyclyl, —O—R¹⁴, —C(═O)—R¹⁴, —C(═O)—O—R¹⁴, —O—C(═O)—R¹⁴,—S(O)_(t)—R¹⁴, —N(R¹⁴)₂, and —C(═O)—N(R¹⁴)₂, wherein each R¹⁴ isindependently selected from H, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₀₋₆alkylaryl, —C₀₋₆alkylheteroaryl, —C₀₋₆alkylcycloalkyl,—C₀₋₆alkylcycloalkenyl or —C₀₋₆alkylheterocyclyl; and t is 0-2; whereineach alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,heterocyclyl and heteroaryl are optionally substituted with one or moreoptional substituents.
 2. The compound according to claim 1 wherein eachR¹³ is independently selected from hydrogen, cyano, nitro, halo,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C(═O)—R¹⁴, —C(═O)—O—R¹⁴,—O—C(═O)—R¹⁴, —N(R¹⁴)₂, and —C(═O)—N(R¹⁴)₂.
 3. The compound according toclaim 1, wherein at least one of L and M is CH.
 4. The compoundaccording to claim 1, wherein L and M are both CH.
 5. The compoundaccording to claim 1, wherein R¹² is hydrogen, cyano, nitro, halo,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C(═O)—R¹⁴, —C(═O)—O—R¹⁴,—O—C(═O)—R¹⁴, —N(R¹⁴)₂, and —C(═O)—N(R¹⁴)₂.
 6. The compound according toclaim 5, wherein R¹² is selected from hydrogen, cyano, nitro, halo,—C₁₋₆alkyl, —C(═O)—R¹⁴, —C(═O)—O—R¹⁴ or —O—C(═O)—R¹⁴, where R¹⁴ ishydrogen or C₁₋₆alkyl.
 7. The compound according to claim 5, wherein R¹²is hydrogen.
 8. The compound according to claim 1, wherein R⁸ is —CONH₂or optionally substituted aryl.
 9. The compound according to claim 1,wherein R¹¹ is —C₂₋₆alkyl, —C₁₋₆perfluoroalkyl or —C₀₋₆alkylaryl. 10.The compound according to claim 1, wherein R⁴ is hydrogen.
 11. Apharmaceutical composition comprising a compound according to claim 1and at least one pharmaceutically acceptable carrier.